Association between trajectories of adherence to endocrine therapy and risk of treated breast cancer recurrence among US nonmetastatic breast cancer survivors.

BACKGROUND: Endocrine therapy is the mainstay treatment for breast cancer (BC) to reduce BC recurrence risk. During the first year of endocrine therapy use, nearly 30% of BC survivors are nonadherent, which may increase BC recurrence risk. This study is to examine the association between endocrine therapy adherence trajectories and BC recurrence risk in nonmetastatic BC survivors. METHODS: This retrospective cohort study included Medicare beneficiaries in the United States (US) with incident nonmetastatic BC followed by endocrine therapy initiation in 2010-2019 US Surveillance, Epidemiology, and End Results linked Medicare data. We calculated monthly fill-based proportion of days covered in the first year of endocrine therapy. We applied group-based trajectory models to identify distinct endocrine therapy adherence patterns. After the end of the first-year endocrine therapy trajectory measurement period, we estimated the risk of time to first treated BC recurrence within 4 years using Cox proportional hazards models. RESULTS: We identified 5 trajectories of adherence to endocrine therapy in BC Stages 0-I subgroup (n = 28,042) and in Stages II-III subgroup (n = 7781). A trajectory of discontinuation before 6 months accounted for 7.0% in Stages 0-I and 5.8% in Stages II-III subgroups, and this trajectory was associated with an increased treated BC recurrence risk compared to nearly perfect adherence (Stages 0-I: adjusted hazard [aHR] = 1.84, 95% CI = 1.46-2.33; Stages II-III: aHR = 1.38, 95% CI = 1.07-1.77). CONCLUSIONS: Nearly 7% of BC survivors who discontinued before completing 6 months of treatment was associated with an increased treated BC recurrence risk compared to those with nearly perfect adherence among Medicare nonmetastatic BC survivors.

Association between trajectories of prescription opioid use and risk of opioid use disorder and overdose among US nonmetastatic breast cancer survivors.

PURPOSE: To examine the association between prescription opioid use trajectories and risk of opioid use disorder (OUD) or overdose among nonmetastatic breast cancer survivors by treatment type. METHODS: This retrospective cohort study included female nonmetastatic breast cancer survivors with at least 1 opioid prescription fill in 2010-2019 Surveillance, Epidemiology and End Results linked Medicare data. Opioid mean daily morphine milligram equivalents (MME) calculated within 1.5 years after initiating active breast cancer therapy. Group-based trajectory models identified distinct opioid use trajectory patterns. Risk of time to first OUD/overdose event within 1 year after the trajectory period was calculated for distinct trajectory groups using Cox proportional hazards models. Analyses were stratified by treatment type. RESULTS: Four opioid use trajectories were identified for each treatment group. For 38,030 survivors with systemic endocrine therapy, 3 trajectories were associated with increased OUD/overdose risk compared with early discontinuation: minimal dose (< 5 MME; adjusted hazard ratio [aHR] = 1.73 [95% CI 1.43-2.09]), very low dose (5-25 MME; 2.67 [2.05-3.48]), and moderate dose (51-90 MME; 6.20 [4.69-8.19]). For 9477 survivors with adjuvant chemotherapy, low-dose opioid use was associated with higher OUD/overdose risk (aHR = 7.33 [95% CI 2.52-21.31]) compared with early discontinuation. For 3513 survivors with neoadjuvant chemotherapy, the differences in OUD/OD risks across the 4 trajectories were not significant. CONCLUSIONS: Among Medicare nonmetastatic breast cancer survivors receiving systemic endocrine therapy or adjuvant chemotherapy, compared with early discontinuation, low-dose or moderate-dose opioid use were associated with six- to sevenfold higher OUD/overdose risk. Breast cancer survivors at high-risk of OUD/overdose may benefit from targeted interventions (e.g., pain clinic referral).

Recent Advances in Group-Based Trajectory Modeling for Clinical Research.

Group-based trajectory modeling (GBTM) identifies groups of individuals following similar trajectories of one or more repeated measures. The categorical nature of GBTM is particularly well suited to clinical psychology and medicine, where patients are often classified into discrete diagnostic categories. This review highlights recent advances in GBTM and key capabilities that remain underappreciated in clinical research. These include accounting for nonrandom subject attrition, joint trajectory and multitrajectory modeling, the addition of the beta distribution to modeling options, associating trajectories with future outcomes, and estimating the probability of future outcomes. Also discussed is an approach to selecting the number of trajectory groups.

Trajectories of Oral Anticoagulation Adherence and Associated Clinical Outcomes During Long-Term Anticoagulation Among Medicare Beneficiaries With Venous Thromboembolism.

BACKGROUND: Little is known about anticoagulation medication nonadherence patterns impacting effectiveness and safety outcomes in clinical practice. OBJECTIVE: We identified adherence trajectories of extended therapy with direct-acting oral anticoagulants (DOACs) and warfarin after 6 months initial anticoagulant therapy among Medicare beneficiaries with venous thromboembolism (VTE). We further assessed the associated recurrent VTE and major bleeding risks. METHODS: Using group-based trajectory models, this retrospective cohort study identified distinct beneficiary subgroups with similar adherence patterns of extended-phase anticoagulant treatment (DOACs or warfarin) for patients with VTE who completed 6 months of initial anticoagulant treatment. We examined associations between adherence trajectories and risks of recurrent VTE and major bleeding using inverse probability treatment weighted Cox proportional hazards models. RESULTS: Compared with no extended treatment, consistently high DOAC adherence was associated with decreased recurrent VTE risk (hazard ratio [HR] = 0.33, 95% confidence interval [CI] = 0.21-0.51) without increased major bleeding risk, and consistently high warfarin adherence was associated with decreased recurrent VTE risk (HR = 0.62, 95% CI = 0.40-0.95) and increased major bleeding risk (HR = 1.64, 95% CI = 1.12-2.41). Gradually declining adherence to DOACs (HR = 1.80, 95% CI = 1.07-3.03) or warfarin (HR = 2.34, 95% CI = 1.57-3.47) was associated with increased bleeding risk with no change in recurrent VTE risk. CONCLUSION AND RELEVANCE: This real-world evidence suggests persistently adhering to extended DOAC therapy is associated with lower recurrent VTE risk without increasing major bleeding among Medicare beneficiaries with VTE. Persistently adhering to extended warfarin therapy was associated with lower recurrent VTE risk but higher major bleeding risk.

Spinal pain in childhood: prevalence, trajectories, and diagnoses in children 6 to 17 years of age.

This study aimed to investigate the trajectories of spinal pain frequency from 6 to 17 years of age and describe the prevalence and frequency of spinal pain and related diagnoses in children following different pain trajectories. First through fifth-grade students from 13 primary schools were followed for 5.5 years. Occurrences of spinal pain were reported weekly via text messages. Children reporting spinal pain were physically evaluated and classified using International Classification of Disease criteria. Trajectories of spinal pain frequency were modeled from age 6 to 17 years with latent class growth analysis. We included data from 1556 children (52.4% female, mean (SD) baseline age = 9.1 (1.9) years) and identified 10,554 weeks of spinal pain in 329,756 weeks of observation. Sixty-three percent of children reported one or more occurrences of spinal pain. We identified five trajectories of spinal pain frequency. Half the children (49.8%) were classified as members of a "no pain" trajectory. The remaining children followed "rare" (27.9%), "rare, increasing" (14.5%), "moderate, increasing" (6.5%), or "early-onset, decreasing" (1.3%) spinal pain trajectories. The most common diagnoses in all trajectory groups were non-specific (e.g., "back pain"). Tissue-specific diagnoses (e.g., muscle strain) were less common and pathologies (e.g., fracture) were rare.  Conclusion: From childhood through adolescence, spinal pain was common and followed heterogeneous courses comprising stable, increasing, and early-onset trajectories. These findings accord with recommendations from adult back pain guidelines that most children with spinal pain can be reassured that they do not have a serious disease and encouraged to stay active. What is Known: • Spinal pain imposes a large burden on individuals and society. • Although many people first experience the condition in childhood, little is known about the developmental trajectories of spinal pain from childhood to adolescence. What is New: • Data from 1556 children and 329,756 participant weeks showed five unique spinal pain trajectories from 6 to 17 years: most children rarely reported spinal pain, while one in five followed increasing or early-onset trajectories. • Most pain occurrences were non-specific; pathological diagnoses were rare.

Classifying Patients with Amyotrophic Lateral Sclerosis by Changes in FVC. A Group-based Trajectory Analysis.

Rationale: A model for stratifying progression of respiratory muscle weakness in amyotrophic lateral sclerosis (ALS) would identify disease mechanisms and phenotypes suitable for future investigations. This study sought to categorize progression of FVC after presentation to an outpatient ALS clinic.Objectives: To identify clinical phenotypes of ALS respiratory progression based on FVC trajectories over time.Methods: We derived a group-based trajectory model from a single-center cohort of 837 patients with ALS who presented between 2006 and 2015. We applied our model to the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database with 7,461 patients with ALS. Baseline characteristics at first visit were used as predictors of trajectory group membership. The primary outcome was trajectory of FVC over time in months.Measurements and Main Results: We found three trajectories of FVC over time, termed "stable low," "rapid progressor," and "slow progressor." Compared with the slow progressors, the rapid progressors had shorter diagnosis delay, more bulbar-onset disease, and a lower ALS Functional Rating Scale-Revised (ALSFRS-R) total score at baseline. The stable low group had a shorter diagnosis delay, lower body mass index, more bulbar-onset disease, lower ALSFRS-R total score, and were more likely to have an ALSFRS-R orthopnea score lower than 4 compared with the slow progressors. We found that projected group membership predicted respiratory insufficiency in the PRO-ACT cohort (concordance statistic = 0.78, 95% CI, 0.76-0.79).Conclusions: We derived a group-based trajectory model for FVC progression in ALS, which validated against the outcome of respiratory insufficiency in an external cohort. Future studies may focus on patients predicted to be rapid progressors.

Adherence trajectories of buprenorphine therapy among pregnant women in a large state Medicaid program in the United States.

PURPOSE: Little is known about the longitudinal patterns of buprenorphine adherence among pregnant women with opioid use disorder, especially when late initiation, nonadherence, or early discontinuation of buprenorphine during pregnancy may increase the risk of adverse outcomes. We aimed to identify distinct trajectories of buprenorphine use during pregnancy, and factors associated with these trajectories in Medicaid-enrolled pregnant women. METHODS: A retrospective cohort study included 2361 Pennsylvania Medicaid enrollees aged 15 to 46 having buprenorphine therapy during pregnancy and a live birth between 2008 and 2015. We used group-based trajectory models to identify buprenorphine use patterns in the 40 weeks prior to delivery and 12 weeks postdelivery. Multivariable multinomial logistic regression models were used to identify factors associated with specific trajectories. RESULTS: Six distinct trajectories were identified. Four groups initiated buprenorphine during the first trimester of the pregnancy (early initiators): 31.6% with persistently high adherence, 15.1% with moderate-to-high adherence, 10.5% with declining adherence, and 16.7% with early discontinuation. Two groups did not initiate buprenorphine until midsecond or third trimester (late initiators): 13.5% had moderate-to-high adherence and 12.6% had low-to-moderate adherence. Factors significantly associated with late initiation and discontinuation were younger age, non-white race, residents of rural counties, fewer outpatient visits, more frequent emergency department visits and hospitalizations, and lower buprenorphine daily dose. CONCLUSIONS: Six buprenorphine treatment trajectories during pregnancy were identified in this population-based Medicaid cohort, with 25% of women initiating buprenorphine late during pregnancy. Understanding trajectories of buprenorphine use and factors associated with discontinuation/nonadherence may guide integration of behavioral treatment with obstetrical/gynecological care to improve buprenorphine treatment during pregnancy.

Patterns of antihypertensive and statin adherence prior to dementia: findings from the adult changes in thought study.

BACKGROUND: Detecting patients with undiagnosed dementia is an important clinical challenge. Changes in medication adherence might represent an early sign of cognitive impairment. We sought to examine antihypertensive and statin adherence trajectories in community-dwelling older adults, comparing people who went on to develop dementia to those who did not. METHODS: We analyzed data from Adult Changes in Thought (ACT), a population-based cohort study embedded within an integrated healthcare delivery system. Analyses included 4368 participants aged ≥65 years who had at least one follow-up visit. Research-quality dementia diagnoses were used to identify cases. We selected non-dementia control visits matched on age, sex, and study cohort that occurred at similar ACT follow-up time as the case's dementia onset; we treated this as the index date. Participants were included if they were prevalent users of either a statin or antihypertensive medication on the first day of follow up - 3 years prior to the index date. Using prescription fill dates and days supply, we calculated daily binary medication availability measures for each participant ('days covered') over 3 years leading up to the index date. We used group-based trajectory models to identify patterns of antihypertensive and statin adherence, and used conditional logistic regression to examine associations between adherence trajectories and dementia. RESULTS: Four trajectories were identified for antihypertensive users (292 cases, 3890 control visits), including near perfect (n = 1877, 36.6% cases, 45.5% controls), high (n = 1840, 43.2% cases, 44.1% controls), moderate (n = 365, 18.5% cases, 8.0% controls) and early poor adherence (n = 100, 1.7% cases, 2.4% controls). Odds of dementia was 3 times greater for those with moderate antihypertensive adherence compared to those with near perfect adherence (adjusted OR 3.0, 95% CI 2.0, 4.3). Four trajectories were identified for statin users (148 cases, 1131 control visits), including high (n = 1004, 75.0% cases, 79.0% controls), moderate (n = 192, 19.6% cases, 14.4% controls), early poor (n = 43, 2.0% cases, 3.5% controls), and delayed poor adherence (n = 40, 3.4% cases, 3.1% controls). No association was detected between statin adherence trajectories and dementia. CONCLUSIONS: Patterns of medication adherence may be useful to identify a subset of people at higher likelihood of developing dementia.

Using the Beta distribution in group-based trajectory models.

BACKGROUND: We demonstrate an application of Group-Based Trajectory Modeling (GBTM) based on the beta distribution. It is offered as an alternative to the normal distribution for modeling continuous longitudinal data that are poorly fit by the normal distribution even with censoring. The primary advantage of the beta distribution is the flexibility of the shape of the density function. METHODS: GBTM is a specialized application of finite mixture modeling designed to identify clusters of individuals who follow similar trajectories. Like all finite mixture models, GBTM requires that the distribution of the data composing the mixture be specified. To our knowledge this is the first demonstration of the use of the beta distribution in GBTM. A case study of a beta-based GBTM analyzes data on the neurological activity of comatose cardiac arrest patients. RESULTS: The case study shows that the summary measure of neurological activity, the suppression ratio, is not well fit by the normal distribution but due to the flexibility of the shape of the beta density function, the distribution of the suppression ratio by trajectory appears to be well matched by the estimated beta distribution by group. CONCLUSIONS: The addition of the beta distribution to the already available distributional alternatives in software for estimating GBTM is a valuable augmentation to extant distributional alternatives.

Who Were the Early Adopters of Dabigatran?: An Application of Group-based Trajectory Models.

BACKGROUND: Variation in physician adoption of new medications is poorly understood. Traditional approaches (eg, measuring time to first prescription) may mask substantial heterogeneity in technology adoption. OBJECTIVE: Apply group-based trajectory models to examine the physician adoption of dabigratran, a novel anticoagulant. METHODS: A retrospective cohort study using prescribing data from IMS Xponent™ on all Pennsylvania physicians regularly prescribing anticoagulants (n=3911) and data on their characteristics from the American Medical Association Masterfile. We examined time to first dabigatran prescription and group-based trajectory models to identify adoption trajectories in the first 15 months. Factors associated with rapid adoption were examined using multivariate logistic regressions. OUTCOMES: Trajectories of monthly share of oral anticoagulant prescriptions for dabigatran. RESULTS: We identified 5 distinct adoption trajectories: 3.7% rapidly and extensively adopted dabigatran (adopting in ≤3 mo with 45% of prescriptions) and 13.4% were rapid and moderate adopters (≤3 mo with 20% share). Two groups accounting for 21.6% and 16.1% of physicians, respectively, were slower to adopt (6-10 mo post-introduction) and dabigatran accounted for <10% share. Nearly half (45.2%) of anticoagulant prescribers did not adopt dabigatran. Cardiologists were much more likely than primary care physicians to rapidly adopt [odds ratio (OR)=12.2; 95% confidence interval (CI), 9.27-16.1] as were younger prescribers (age 36-45 y: OR=1.49, 95% CI, 1.13-1.95; age 46-55: OR=1.34, 95% CI, 1.07-1.69 vs. >55 y). CONCLUSIONS: Trajectories of physician adoption of dabigatran were highly variable with significant differences across specialties. Heterogeneity in physician adoption has potential implications for the cost and effectiveness of treatment.

Trajectories of Diabetes Medication Adherence and Hospitalization Risk: A Retrospective Cohort Study in a Large State Medicaid Program.

BACKGROUND: Numerous interventions are available to boost medication adherence, but the targeting of these interventions often relies on crude measures of poor adherence. Group-based trajectory models identify individuals with similar longitudinal prescription filling patterns. Identifying distinct adherence trajectories may be more useful for targeting interventions, although the association between adherence trajectories and clinical outcomes is unknown. OBJECTIVE: To examine the association between adherence trajectories for oral hypoglycemics and subsequent hospitalizations among diabetes patients. DESIGN: Retrospective cohort study. PATIENTS: A total of 16,256 Pennsylvania Medicaid enrollees, non-dually eligible for Medicare, initiating oral hypoglycemics between 2007 and 2009. MAIN MEASURES: We used group-based trajectory models to identify trajectories of oral hypoglycemics in the 12 months post-treatment initiation, using monthly proportion of days covered (PDC) as the adherence measure. Multivariable Cox proportional hazard models were used to examine the association between trajectories and time to first diabetes-related hospitalization/emergency department (ED) visits in the following year. We used the C-index to compare prediction performance between adherence trajectories and dichotomous cutpoints (annual PDC <80 vs. ≥80 %). RESULTS: The mean annual PDC was 0.58 (SD 0.32). Seven trajectories were identified: perfect adherers (9 % of the cohort), nearly perfect adherers (31.4 %), moderate adherers (21.0 %), low adherers (11.0 %), late discontinuers (6.8 %), early discontinuers (9.7 %), and non-adherers with only one fill (11.1 %). Compared to perfect adherers, trajectories of moderate adherers (HR = 1.48, 95 % CI 1.25, 1.75), low adherers (HR = 1.51, 95 % CI 1.25, 1.83), and non-adherers with only one fill (HR = 1.35, 95 % CI 1.09, 1.67) had greater risk of diabetes-related hospitalizations/ED visits. Predictive accuracy was improved using trajectories compared to dichotomized cutpoints (C-index = 0.714 vs. 0.652). CONCLUSIONS: Oral hypoglycemic treatment trajectories were highly variable in this large Medicaid cohort. Low and moderate adherers and those filling only one prescription had a modestly higher risk of hospitalizations/ED visits compared to perfect adherers. Trajectory models may be valuable in identifying specific non-adherence patterns for targeting interventions.

Longitudinal predictors of cannabis use and dependence in offspring from families at ultra high risk for alcohol dependence and in control families.

Cannabis use is common among adolescents. Identification of the factors associated with continued heavy use into young adulthood and development of cannabis abuse and dependence is of considerable importance. The role of familial risk for addiction and an associated endophenotype, P300 amplitude, has not previously been related to cannabis use and dependence. A prospective longitudinal study spanning childhood and young adulthood provided the opportunity for exploring these factors, along with genetic variation, in the cannabis use behaviors of 338 young adult offspring from high and low familial risk for alcohol dependence families (ages 19-30). P300 data were collected multiple times in childhood. The association between young adult patterns of cannabis use or cannabis abuse/dependence was tested with genetic variation in the cannabinoid gene, CNR1, the ANKK1-DRD2 gene, and childhood developmental trajectories of P300. Young adult patterns of cannabis use was characterized by three patterns: (i) no use throughout; (ii) declining use from adolescence through young adulthood; and (iii) frequent use throughout. Following the low P300 trajectory in childhood predicted cannabis abuse and dependence by young adulthood. A four SNP ANKK1-DRD2 haplotype (G-G-G-C) was found to be significantly associated with the frequency of use patterns (P = 0.0008). Although CNR1 variation overall was not significantly associated with these patterns, among individuals with cannabis abuse/dependence the presence of one or both copies of the rs806368 A > G minor allele conferred a 5.4-fold increase (P = 0.003) in the likelihood that they would be in the frequent and persistent use group rather than the declining use group.

Effectiveness of a physical activity and weight loss intervention for middle-aged women: healthy bodies, healthy hearts randomized trial.

BACKGROUND: Physical inactivity is a significant risk factor for cardiovascular disease and remains highly prevalent in middle-aged women. OBJECTIVE: We hypothesized that an interventionist-led (IL), primary-care-based physical activity (PA) and weight loss intervention would increase PA levels and decrease weight to a greater degree than a self-guided (SG) program. DESIGN: We conducted a randomized trial. PARTICIPANTS: Ninety-nine inactive women aged 45-65 years and with BMI ≥ 25 kg/m(2) were recruited from three primary care clinics. INTERVENTIONS: The interventionist-led (IL) group (n = 49) had 12 weekly sessions of 30 min discussions with 30 min of moderate-intensity PA. The self-guided (SG) group (n = 50) received a manual for independent use. MAIN MEASURES: Assessments were conducted at 0, 3, and 12 months; PA and weight were primary outcomes. Weight was measured with a standardized protocol. Leisure PA levels were assessed using the Modifiable Activity Questionnaire. Differences in changes by group were analyzed with a t-test or Wilcoxon rank-sum test. Mixed models were used to analyze differences in changes of outcomes by group, using an intention-to-treat principle. KEY RESULTS: Data from 98 women were available for analysis. At baseline, mean (SD) age was 53.9 (5.4) years and 37 % were black. Mean weight was 92.3 (17.7) kg and mean BMI was 34.7 (5.9) kg/m(2). Median PA level was 2.8 metabolic equivalent hours per week (MET-hour/week) (IQR 0.0, 12.0). At 3 months, IL women had a significantly greater increase in PA levels (7.5 vs. 1.9 MET-hour/week; p = 0.02) than SG women; there was no significant difference in weight change. At 12 months, the difference between groups was no longer significant (4.7 vs. 0.7 MET-hour/week; p = 0.38). Mixed model analysis showed a significant (p = 0.048) difference in PA change between groups at 3 months only. CONCLUSIONS: The IL intervention was successful in increasing the physical activity levels of obese, inactive middle-aged women in the short-term. No significant changes in weight were observed.

ACN9 and alcohol dependence: family-based association analysis in multiplex alcohol dependence families.

A previous genome-wide linkage study of alcohol dependence (AD) in the Pittsburgh-based multiplex family study found suggestive evidence for linkage on Chromosome 7q, a region in which the ACN9 gene is located. Using the same two generation Pittsburgh family data in which linkage was found, data for a third generation was added. The expanded sample included 133 pedigrees with 995 individuals. Finer mapping was undertaken using six SNPs extending from rs1917939 to rs13475 with minor allele frequency (MAF) ≥0.15 and pair-wise linkage disequilibrium (LD) of r(2) <0.8 using the HapMap CEU population. Binary affection status, visual, and auditory P300 data were tested for family-based association. Family-based analyses found all six SNPs associated with affected status. Three SNPs are located upstream of the gene, two SNPs are within intron 1 and one is in Exon 4. FBAT P-values for the six SNPs ranged between 0.05 and 0.0005. Haplotype analysis revealed one four-SNP block formed by rs10499934, rs7794886, rs12056091, and rs13475 with an overall significant association at P = 0.0008. Analysis of visual P300 amplitude data, a known endophenotype of alcohol dependence risk, revealed a significant association for SNPs within intron 1 and exon 4 under a dominant model of transmission. Family-based association analysis shows the ACN9 gene significantly associated with alcohol dependence and P300 amplitude variation. The potential importance of the ACN9 gene for AD risk may be related to its role in gluconeogenesis which may be involved in the regulation of alcohol metabolism.

Association between Opioid-Benzodiazepine Trajectories and Injurious Fall Risk among US Medicare Beneficiaries.

Background/Objectives: Concurrent opioid (OPI) and benzodiazepine (BZD) use may exacerbate injurious fall risk (e.g., falls and fractures) compared to no use or use alone. Yet, patients may need concurrent OPI-BZD use for co-occurring conditions (e.g., pain and anxiety). Therefore, we examined the association between longitudinal OPI-BZD dosing patterns and subsequent injurious fall risk. Methods: We conducted a retrospective cohort study including non-cancer fee-for-service Medicare beneficiaries initiating OPI and/or BZD in 2016-2018. We identified OPI-BZD use patterns during the 3 months following OPI and/or BZD initiation (i.e., trajectory period) using group-based multi-trajectory models. We estimated the time to first injurious falls within the 3-month post-trajectory period using inverse-probability-of-treatment-weighted Cox proportional hazards models. Results: Among 622,588 beneficiaries (age ≥ 65 = 84.6%, female = 58.1%, White = 82.7%; having injurious falls = 0.45%), we identified 13 distinct OPI-BZD trajectories: Group (A): Very-low OPI-only (early discontinuation) (44.9% of the cohort); (B): Low OPI-only (rapid decline) (15.1%); (C): Very-low OPI-only (late discontinuation) (7.7%); (D): Low OPI-only (gradual decline) (4.0%); (E): Moderate OPI-only (rapid decline) (2.3%); (F): Very-low BZD-only (late discontinuation) (11.5%); (G): Low BZD-only (rapid decline) (4.5%); (H): Low BZD-only (stable) (3.1%); (I): Moderate BZD-only (gradual decline) (2.1%); (J): Very-low OPI (rapid decline)/Very-low BZD (late discontinuation) (2.9%); (K): Very-low OPI (rapid decline)/Very-low BZD (increasing) (0.9%); (L): Very-low OPI (stable)/Low BZD (stable) (0.6%); and (M): Low OPI (gradual decline)/Low BZD (gradual decline) (0.6%). Compared with Group (A), six trajectories had an increased 3-month injurious falls risk: (C): HR = 1.78, 95% CI = 1.58-2.01; (D): HR = 2.24, 95% CI = 1.93-2.59; (E): HR = 2.60, 95% CI = 2.18-3.09; (H): HR = 2.02, 95% CI = 1.70-2.40; (L): HR = 2.73, 95% CI = 1.98-3.76; and (M): HR = 1.96, 95% CI = 1.32-2.91. Conclusions: Our findings suggest that 3-month injurious fall risk varied across OPI-BZD trajectories, highlighting the importance of considering both dose and duration when assessing injurious fall risk of OPI-BZD use among older adults.

Trajectories of adherence to extended treatment with direct oral anticoagulants and risks of recurrent venous thromboembolism and major bleeding.

BACKGROUND: Little is known about medication adherence patterns and their association with effectiveness and safety among patients with venous thromboembolism (VTE) receiving direct oral anticoagulant (DOAC) therapy beyond 3-6 months of initial treatment. OBJECTIVE: To examine the associations between adherence trajectories of extended treatment with DOAC and the risks of recurrent VTE and major bleeding among patients with VTE. METHODS: We conducted a retrospective cohort study of patients with incident VTE who completed 6 months of initial anticoagulant treatment and received either DOAC extended therapy or no extended therapy using MarketScan Commercial and Medicare Supplemental databases (2013-2019). We used group-based trajectory models to identify distinct adherence patterns during extended treatment. Using inverse probability treatment weighted Cox proportional hazards models, we examined the association between the adherence trajectories and the risks of recurrent VTE and major bleeding. RESULTS: Among 10,960 patients with extended treatment with DOACs (rivaroxaban, apixaban, dabigatran, edoxaban) and 5,133 patients with no extended treatment, we identified 4 distinct trajectories (consistently high, gradually declining, rapidly declining, and no extended treatment). Compared with the no extended treatment group, the groups with consistently high adherence (hazard ratio = 0.09, 95% CI = 0.05-0.17) and with gradually declining adherence (0.13, 0.03-0.53) showed decreased recurrent VTE risk without increased major bleeding risk (consistently high adherence 1.19, 0.71-1.99; gradually declining adherence 1.96, 0.81-4.70). There was no difference in the risk of recurrent VTE (0.34, 0.10-1.16) for the group with rapidly declining adherence, but this group was associated with increased major bleeding risk (2.65, 1.01-6.92). CONCLUSIONS: Our findings underscore the clinical importance of continuing and remaining adherent to extended DOAC treatment without increased major bleeding risk for patients with VTE. DISCLOSURES: This research was supported by the BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program. The funding source had no role in the design, collection, analysis, or interpretation of the data or the decision to submit the article for publication. Dr Lo-Ciganic reported receiving research funding from Merck Sharp & Dohme Corp. Dr Dietrich reported receiving honorarium for training and education from BMS/Pfizer. Dr DeRemer is a stockholder of Portola Pharmaceuticals and reported receiving personal fees for advisory board meeting from BMS. No other disclosures were reported.

Pain trajectories of nursing home residents.

BACKGROUND: Understanding changes in nursing home (NH) resident pain over time would provide a more informed perspective, allowing opportunities to alter the course of illness, plan care, and set priorities. Therefore, the purpose of this analysis was to identify and characterize clinically meaningful, dynamic pain trajectories in NH residents. METHODS: Retrospective longitudinal analysis of NH resident pain scores with a length of stay >100 days (N = 4864). Group-based trajectory modeling was applied to Minimum Data Set 3.0 assessments to identify pain trajectories. Trajectories were then characterized using unadjusted and adjusted cross-sectional associations between residents' demographic and clinical characteristics and their pain trajectory. RESULTS: We identified four distinct trajectories: (1) consistent pain absence (48.9%), (2) decreasing-increasing pain presence (21.8%), (3) increasing-decreasing pain presence (15.3%), and (4) persistent pain presence (14.0%). Demographics of younger age and living in a rural area were associated with the persistent pain presence trajectory. Clinical variables of obesity and intact cognition were associated with being in the persistent pain presence trajectory. A smaller proportion of residents with moderately or severely impaired cognition were in any of the trajectory groups with pain. CONCLUSIONS: We identified and characterized four pain trajectories among NH residents, including persistent pain presence which was associated with demographic characteristics (younger, female, rural) and clinical factors (obese, fracture, contracture). Moreover, residents with a diagnosis of Alzheimer's disease or dementia were less likely to be in any of the three trajectories with pain, likely representing the difficulty in evaluating pain in these residents. It is important that NH staff understand, recognize, and respond to the factors associated with the identified pain trajectories to improve mitigation of potentially persistent pain (e.g., hip fracture, contracture) or improve proxy pain assessment skills for residents at risk for under reporting of pain (e.g., Alzheimer's Disease).

Trajectories of adherence to extended treatment with warfarin and risks of recurrent venous thromboembolism and major bleeding.

Background: Little is published about warfarin therapy adherence patterns beyond 6 months of initial anticoagulant treatment and their association with effectiveness and safety for patients with venous thromboembolism (VTE). Objectives: To compare the risks of recurrent VTE and major bleeding during extended treatment between adherence patterns using MarketScan Commercial and Medicare Supplemental databases (2013-2019). Methods: In a retrospective cohort study, we included patients with incident VTE who completed an initial 6-month anticoagulant treatment and received either warfarin or no extended therapy. Group-based trajectory models were used to identify distinct extended treatment trajectories. Associations between the trajectories and risk of hospitalization due to recurrent VTE and major bleeding were assessed using inverse probability treatment-weighted Cox proportional hazards models. Results: Compared with no extended treatment, consistently high warfarin adherence was associated with a significantly decreased risk of hospitalization due to recurrent VTE (hazard ratio [HR] = 0.23; 95% CI, 0.12-0.45), but gradually (HR = 0.29; 95CI, 0.08-1.06) or rapidly declining (HR = 0.14; 95% CI, 0.02-1.24) adherence showed no association with the risk of hospitalization due to recurrent VTE. Compared with no extended treatment, warfarin extended therapy was associated with an increased risk of hospitalization due to major bleeding regardless of adherence patterns (consistently high: HR = 2.08; 95% CI, 1.18-3.64, gradually declining: HR = 2.10; 95% CI, 0.74-5.95, and rapidly declining: HR = 9.19; 95% CI, 4.38-19.29). However, compared with rapidly declining adherence, consistently high (HR = 0.23; 95% CI, 0.11-0.47) and gradually declining (HR = 0.23; 95% CI, 0.08-0.64) adherence were associated with decreased risk of hospitalization due to major bleeding. Conclusion: The findings indicated that consistently high adherence to extended warfarin treatment was associated with a decreased risk of hospitalization due to recurrent VTE but an increased risk of hospitalization due to major bleeding compared with no extended treatment.

Distressed partners and caregivers do not recover easily: adjustment trajectories among partners and caregivers of cancer survivors.

BACKGROUND: Although a number of cross-sectional studies document the distress experienced by partners and caregivers of cancer survivors, few have considered their potential differential patterns of adjustment over time. PURPOSE: Identify distinct trajectories of anxiety and depression among partners and caregivers of cancer survivors and predictors of these trajectories. METHODS: Participants completed a survey to examine the impact of caring for, or living with, a cancer survivor at 6, 12, and 24 months post-survivor diagnosis. Anxiety and depression were measured using the Hospital Anxiety and Depression Scale (N(anxiety) = 510; N(depression) = 511). RESULTS: Anxiety trajectories included: no anxiety (15.1% scored <3; 37.8% scored 3-5); chronic, borderline anxiety (33.2%); and chronic, clinical anxiety (13.9%). The depression trajectories were: no depression (38.9% scored <2; 31.5% scored around 3); a sustained score of 7 (25.5%); and chronic, clinical depression (4.1%). Variables associated with the trajectories included most of the psychosocial variables. CONCLUSIONS: Findings highlight that most caregivers maintained their baseline level of distress, which is particularly concerning for participants reporting chronic anxiety or depression.

Long-acting beta-agonists and the risk of intensive care unit admission in children.

OBJECTIVE: A possible association between long-acting beta-agonists (LABA) and severe asthma exacerbations including death remains controversial. We examined whether LABA in the setting of combination therapy with inhaled corticosteroids (ICS) increase the risk of near-fatal asthma in children using a case-control study design. METHODS: Medical records from admissions for asthma exacerbations in children 4-18 years of age during the 2005 calendar year at Children's Hospital of Pittsburgh of UPMC were reviewed. Cases and controls were determined by pediatric intensive care unit (PICU) and floor admission, respectively. Exposure was defined by LABA use in combination with ICS versus ICS alone. RESULTS: Records from 85 PICU and 96 pediatric floor admissions were reviewed. LABA use in combination with ICS did not increase the risk of PICU admission (odds ratio 1.07, 95% CI 0.46-2.52) compared to ICS only without LABA. After adjusting for demographics, asthma severity, history of PICU admissions, and concurrent infection, LABA/ICS use still did not increase the risk of PICU admission (adjusted odds ratio 0.84, 95% CI 0.26-2.76) compared to ICS alone. There were no deaths and five intubations within the study period. CONCLUSIONS: The combination of LABA and ICS did not appear to increase the risk of near-fatal asthma in children.