Opioid prescription and risk of atrial fibrillation in younger veterans.

BACKGROUND: Opioids may play a part in the development of atrial fibrillation (AF). Understanding the relationship between opioid exposure and AF can help providers better assess the risk and benefits of prescribing opioids. OBJECTIVE: To assess the incidence of AF as a function of prescribed opioids and opioid type. DESIGN: We performed unadjusted and adjusted time-updated Cox regressions to assess the association between opioid exposure and incident AF. PARTICIPANTS: The national study sample was comprised of Veterans enrolled in the Veterans Health Administration (VHA) who served in support of post-9/11 operations. MAIN MEASURES: The main predictor of interest was prescription opioid exposure, which was treated as a time-dependent variable. The first was any opioid exposure (yes/no). Secondary was opioid type. The outcome, incident AF, was identified through ICD-9-CM diagnostic codes at any primary care visit after the baseline period. KEY RESULTS: A total of 609,763 veterans (mean age: 34 years and 13.24% female) were included in our study. Median follow-up time was 4.8 years. Within this cohort, 124,395 veterans (20.40%) were prescribed an opioid. A total of 1,455 Veterans (0.24%) were diagnosed with AF. In adjusted time-updated Cox regressions, the risk of incident AF was higher in the veterans prescribed opioids (hazard ratio [HR]: 1.47; 95% confidence interval [CI]: 1.38-1.57). In adjusted time-updated Cox regressions, both immunomodulating and nonimmunomodulating opioid type was associated with increased risk of incident AF (HR: 1.40; 95% CI: 1.25-1.57 and HR: 1.49; 95% CI: 1.39-1.60), compared to no opioid use, respectively. CONCLUSIONS: Our findings suggest opioid prescription may be a modifiable risk factor for the development of AF.

An Introduction and Practical Guide to Strategies for Analyzing Longitudinal Data in Clinical Trials of Smoking Cessation Treatment: Beyond Dichotomous Point-Prevalence Outcomes.

Conceptualizing tobacco dependence as a chronic relapsing condition suggests the need to use analytic strategies that reflect that premise. However, clinical trials for smoking cessation typically define the primary endpoint as a measure of abstinence at a single timepoint distal to the intervention, typically 3-12 months. This reinforces the concept of tobacco outcomes as a dichotomous state-one is, or is not, abstinent. Fortunately, there are several approaches available to handle longitudinal data that reflect the relapsing and remitting nature of tobacco use during treatment studies. In this paper, sponsored by the Society for Research on Nicotine and Tobacco's Treatment Research Network, we present an introductory overview of these techniques and their application in smoking cessation clinical trials. Topics discussed include models to examine abstinence outcomes (eg, trajectory models of abstinence, models for transitions in smoking behavior, models for time to event), models that examine reductions in tobacco use, and models to examine joint outcomes (eg, examining changes in the use of more than one tobacco product). Finally, we discuss three additional relevant topics (ie, heterogeneity of effects, handling missing data, and power and sample size) and provide summary information about the type of model that can be used based on the type of data collected and the focus of the study. We encourage investigators to familiarize themselves with these techniques and use them in the analysis of data from clinical trials of smoking cessation treatment. Implications Clinical trials of tobacco dependence treatment typically measure abstinence 3-12 months after participant enrollment. However, because smoking is a chronic relapsing condition, these measures of intervention success may not accurately reflect the common trajectories of tobacco abstinence and relapse. Several analytical techniques facilitate this type of outcome modeling. This paper is meant to be an introduction to these concepts and techniques to the global nicotine and tobacco research community including which techniques can be used for different research questions with visual summaries of which types of models can be used for different types of data and research questions.

The dementia care study (D-CARE): Recruitment strategies and demographic characteristics of participants in a pragmatic randomized trial of dementia care.

INTRODUCTION: Pragmatic research studies that include diverse dyads of persons living with dementia (PLWD) and their family caregivers are rare. METHODS: Community-dwelling dyads were recruited for a pragmatic clinical trial evaluating three approaches to dementia care. Four clinical trial sites used shared and site-specific recruitment strategies to enroll health system patients. RESULTS: Electronic health record (EHR) queries of patients with a diagnosis of dementia and engagement of their clinicians were the main recruitment strategies. A total of 2176 dyads were enrolled, with 80% recruited after the onset of the pandemic. PLWD had a mean age of 80.6 years (SD 8.5), 58.4% were women, and 8.8% were Hispanic/Latino, and 11.9% were Black/African American. Caregivers were mostly children of the PLWD (46.5%) or spouses/partners (45.2%), 75.8% were women, 9.4% were Hispanic/Latino, and 11.6% were Black/African American. DISCUSSION: Health systems can successfully enroll diverse dyads in a pragmatic clinical trial.

A Randomized Trial of a Multifactorial Strategy to Prevent Serious Fall Injuries.

BACKGROUND: Injuries from falls are major contributors to complications and death in older adults. Despite evidence from efficacy trials that many falls can be prevented, rates of falls resulting in injury have not declined. METHODS: We conducted a pragmatic, cluster-randomized trial to evaluate the effectiveness of a multifactorial intervention that included risk assessment and individualized plans, administered by specially trained nurses, to prevent fall injuries. A total of 86 primary care practices across 10 health care systems were randomly assigned to the intervention or to enhanced usual care (the control) (43 practices each). The participants were community-dwelling adults, 70 years of age or older, who were at increased risk for fall injuries. The primary outcome, assessed in a time-to-event analysis, was the first serious fall injury, adjudicated with the use of participant report, electronic health records, and claims data. We hypothesized that the event rate would be lower by 20% in the intervention group than in the control group. RESULTS: The demographic and baseline characteristics of the participants were similar in the intervention group (2802 participants) and the control group (2649 participants); the mean age was 80 years, and 62.0% of the participants were women. The rate of a first adjudicated serious fall injury did not differ significantly between the groups, as assessed in a time-to-first-event analysis (events per 100 person-years of follow-up, 4.9 in the intervention group and 5.3 in the control group; hazard ratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P = 0.25). The rate of a first participant-reported fall injury was 25.6 events per 100 person-years of follow-up in the intervention group and 28.6 events per 100 person-years of follow-up in the control group (hazard ratio, 0.90; 95% CI, 0.83 to 0.99; P = 0.004). The rates of hospitalization or death were similar in the two groups. CONCLUSIONS: A multifactorial intervention, administered by nurses, did not result in a significantly lower rate of a first adjudicated serious fall injury than enhanced usual care. (Funded by the Patient-Centered Outcomes Research Institute and others; STRIDE ClinicalTrials.gov number, NCT02475850.).

Successful Optimization of Tobacco Dependence Treatment in the Emergency Department: A Randomized Controlled Trial Using the Multiphase Optimization Strategy.

STUDY OBJECTIVE: Tobacco dependence treatment initiated in the hospital emergency department (ED) is effective. However, trials typically use multicomponent interventions, making it difficult to distinguish specific components that are effective. In addition, interactions between components cannot be assessed. The Multiphase Optimization Strategy allows investigators to identify these effects. METHODS: We conducted a full-factorial, 24 or 16-condition optimization trial in a busy hospital ED to examine the performance of 4 tobacco dependence interventions: a brief negotiation interview; 6 weeks of nicotine replacement therapy with the first dose delivered in the ED; active referral to a telephone quitline; and enrollment in SmokefreeTXT, a free short-messaging service program. Study data were analyzed with a novel mixed methods approach to assess clinical efficacy, cost-effectiveness, and qualitative participant feedback. The primary endpoint was tobacco abstinence at 3 months, verified by exhaled carbon monoxide using a Bedfont Micro+ Smokerlyzer. RESULTS: Between February 2017 and May 2019, we enrolled 1,056 adult smokers visiting the ED. Odd ratios (95% confidence intervals) from the primary analysis of biochemically confirmed abstinence rates at 3 months for each intervention, versus control, were: brief negotiation interview, 1.8 (1.1, 2.8); nicotine replacement therapy, 2.1 (1.3, 3.2); quitline, 1.4 (0.9, 2.2); SmokefreeTXT, 1.1 (0.7, 1.7). There were no statistically significant interactions among components. Economic and qualitative analyses are in progress. CONCLUSION: The brief negotiation interview and nicotine replacement therapy were efficacious. This study is the first to identify components of ED-initiated tobacco dependence treatment that are individually effective. Future work will address the scalability of the brief negotiation interview and nicotine replacement therapy by offering provider-delivered brief negotiation interviews and nicotine replacement therapy prescriptions.

URINE TOXICOLOGY PROFILES OF EMERGENCY DEPARTMENT PATIENTS WITH UNTREATED OPIOID USE DISORDER: A MULTI-SITE VIEW.

BACKGROUND: Opioid overdose deaths in 2021 were the highest ever, driven by fentanyl and polysubstance use. OBJECTIVE: The aim of the study was to characterize drug use, assessed by urine drug screens (UDSs), in patients with untreated opioid use disorder (OUD) presenting to 28 emergency departments (EDs) nationally and by region. METHODS: We analyzed UDSs from patients enrolled in the CTN-0099 ED-INNOVATION (Emergency Department-Initiated Buprenorphine Validation) trial between July 12, 2020 and March 9, 2022. Participants were adult ED patients with OUD not engaged in addiction treatment with a UDS positive for an opioid, but negative for methadone. Sites were divided into "East" and "West" regions. RESULTS: A UDS was available for all 925 enrolled participants, 543 from East and 382 from West. Fentanyl was in 702 specimens (76%) (n = 485 [89%] East vs. n = 217 [57%] West; p < 0.01) and was the only opioid in 269 (29%). After fentanyl, the most common opioids were morphine (presumably heroin; n = 411 [44%]; n = 192 [35%] East vs. n = 219 [57%] West; p < 0.01) and buprenorphine (n = 329 [36%]; n = 186 [35%] East vs. n = 143 [37%] West; p = 0.32). The most common drugs found with opioids were stimulants (n = 545 [59%]), tetrahydrocannabinol (n = 417 [45%]), and benzodiazepines (n = 151 [16%]). Amphetamine-type stimulants were more common in West (n = 209 [55%] vs. East (n = 125 [23%]). Cocaine was more common in East (n = 223 [41%]) vs. West (n = 82 [21%]). The presence of multiple drugs was common (n = 759 [82%]). CONCLUSIONS: Most participants had UDS specimens containing multiple substances; a high proportion had fentanyl, stimulants, and buprenorphine. Regional differences were noted. Given the increased risk of death with fentanyl and polysubstance use, ED providers should be providing risk reduction counseling, treatment, and referral.

Gender Differences in Guideline-Directed Medical Therapy for Cardiovascular Disease Among Young Veterans.

BACKGROUND: There is an increasing burden of cardiovascular disease, including coronary artery disease (CAD) and heart failure (HF), among women Veterans. Clinical practice guidelines recommend multiple pharmacotherapies that can reduce risk of mortality and adverse cardiovascular outcomes. OBJECTIVE: To determine if there are disparities in the use of guideline-directed medical therapy by gender among Veterans with incident CAD and HF. DESIGN: Retrospective. PARTICIPANTS: Veterans (934,504; 87.8% men and 129,469; 12.2% women) returning from Operations Enduring Freedom, Iraqi Freedom, and New Dawn. MAIN MEASURES: Differences by gender in the prescription of Class 1, Level of Evidence A guideline-directed medical therapy among patients who developed incident CAD and HF at 30 days, 90 days, and 12 months after diagnosis. For CAD, medications included statins and antiplatelet therapy. For HF, medications included beta-blockers and renin-angiotensin-aldosterone system inhibitors. KEY RESULTS: Overall, women developed CAD and HF at a younger average age than men (mean 45.8 vs. 47.7 years, p<0.001; and 43.7 vs. 45.4 years, p<0.02, respectively). In the 12 months following a diagnosis of incident CAD, the odds of a woman receiving a prescription for at least one CAD drug was 0.85 (95% confidence interval [CI], 0.68-1.08) compared to men. In the 12 months following a diagnosis of incident HF, the odds of a woman receiving at least one HF medication was 0.54 (95% CI, 0.37-0.79) compared to men. CONCLUSIONS: Despite guideline recommendations, young women Veterans have approximately half the odds of being prescribed guideline-directed medical therapy within 1-year after a diagnosis of HF. These results highlight the need to develop targeted strategies to minimize gender disparities in CVD care to prevent adverse outcomes in this young and growing population.

Sample size calculation in hierarchical 2×2 factorial trials with unequal cluster sizes.

Motivated by a suicide prevention trial with hierarchical treatment allocation (cluster-level and individual-level treatments), we address the sample size requirements for testing the treatment effects as well as their interaction. We assume a linear mixed model, within which two types of treatment effect estimands (controlled effect and marginal effect) are defined. For each null hypothesis corresponding to an estimand, we derive sample size formulas based on large-sample z-approximation, and provide finite-sample modifications based on a t-approximation. We relax the equal cluster size assumption and express the sample size formulas as functions of the mean and coefficient of variation of cluster sizes. We show that the sample size requirement for testing the controlled effect of the cluster-level treatment is more sensitive to cluster size variability than that for testing the controlled effect of the individual-level treatment; the same observation holds for testing the marginal effects. In addition, we show that the sample size for testing the interaction effect is proportional to that for testing the controlled or the marginal effect of the individual-level treatment. We conduct extensive simulations to validate the proposed sample size formulas, and find the empirical power agrees well with the predicted power for each test. Furthermore, the t-approximations often provide better control of type I error rate with a small number of clusters. Finally, we illustrate our sample size formulas to design the motivating suicide prevention factorial trial. The proposed methods are implemented in the R package H2x2Factorial.

Design and Implementation of an Agitation Code Response Team in the Emergency Department.

STUDY OBJECTIVE: Agitation, defined as excessive psychomotor activity leading to violent and aggressive behavior, is becoming more prevalent in the emergency department (ED) amidst a strained behavioral health system. Team-based interventions have demonstrated promise in promoting de-escalation, with the hope of minimizing the need for invasive techniques, like physical restraints. This study aimed to evaluate an interprofessional code response team intervention to manage agitation in the ED with the goal of decreasing physical restraint use. METHODS: This quality improvement study occurred over 3 phases, representing stepwise rollout of the intervention: (1) preimplementation (phase I) to establish baseline outcome rates; (2) design and administrative support (phase II) to conduct training and protocol design; and (3) implementation (phase III) of the code response team. An interrupted time-series analysis was used to compare trends between phases to evaluate the primary outcome of physical restraint orders occurring during the study period. RESULTS: Within the 634,578 ED visits over a 5-year period, restraint use significantly declined sequentially over the 3 phases (1.1%, 0.9%, and 0.8%, absolute change -0.3% between phases I and III, 95% confidence interval [CI] -0.4% to 0.3%), which corresponded to a 27.3% proportionate decrease in restraint rates between phases I and III. For the interrupted time-series analysis, there was a significantly decreasing slope in biweekly restraints in phase II compared to phase I (slope, -0.05 restraints per 1,000 ED visits per 2-week period, 95% CI -0.07 to -0.03), which was sustained in an incremental fashion in phase III (slope, -0.05, 95% CI -0.07 to -0.02). CONCLUSION: With the implementation of a structured agitation code response team intervention combined with design and administrative support, a decreased rate of physical restraint use occurred over a 5-year period. Results suggest that investment in organizational change, along with interprofessional collaboration during the management of agitated patients in the ED, can lead to sustained reductions in the use of an invasive and potentially harmful measure on patients.

Impact of complex, partially nested clustering in a three-arm individually randomized group treatment trial: A case study with the wHOPE trial.

BACKGROUND/AIMS: When participants in individually randomized group treatment trials are treated by multiple clinicians or in multiple group treatment sessions throughout the trial, this induces partially nested clusters which can affect the power of a trial. We investigate this issue in the Whole Health Options and Pain Education trial, a three-arm pragmatic, individually randomized clinical trial. We evaluate whether partial clusters due to multiple visits delivered by different clinicians in the Whole Health Team arm and dynamic participant groups due to changing group leaders and/or participants across treatment sessions during treatment delivery in the Primary Care Group Education arm may impact the power of the trial. We also present a Bayesian approach to estimate the intraclass correlation coefficients. METHODS: We present statistical models for each treatment arm of Whole Health Options and Pain Education trial in which power is estimated under different intraclass correlation coefficients and mapping matrices between participants and clinicians or treatment sessions. Power calculations are based on pairwise comparisons. In practice, sample size calculations depend on estimates of the intraclass correlation coefficients at the treatment sessions and clinician levels. To accommodate such complexities, we present a Bayesian framework for the estimation of intraclass correlation coefficients under different participant-to-session and participant-to-clinician mapping scenarios. We simulated continuous outcome data based on various clinical scenarios in Whole Health Options and Pain Education trial using a range of intraclass correlation coefficients and mapping matrices and used Gibbs samplers with conjugate priors to obtain posteriors of the intraclass correlation coefficients under those different scenarios. Posterior means and medians and their biases are calculated for the intraclass correlation coefficients to evaluate the operating characteristics of the Bayesian intraclass correlation coefficient estimators. RESULTS: Power for Whole Health Team versus Primary Care Group Education is sensitive to the intraclass correlation coefficient in the Whole Health Team arm. In these two arms, an increased number of clinicians, more evenly distributed workload of clinicians, or more homogeneous treatment group sizes leads to increased power. Our simulation study for the intraclass correlation coefficient estimation indicates that the posterior mean intraclass correlation coefficient estimator has less bias when the true intraclass correlation coefficients are large (i.e. 0.10), but when the intraclass correlation coefficient is small (i.e. 0.01), the posterior median intraclass correlation coefficient estimator is less biased. CONCLUSION: Knowledge of intraclass correlation coefficients and the structure of clustering are critical to the design of individually randomized group treatment trials with partially nested clusters. We demonstrate that the intraclass correlation coefficient of the Whole Health Team arm can affect power in the Whole Health Options and Pain Education trial. A Bayesian approach provides a flexible procedure for estimating the intraclass correlation coefficients under complex scenarios. More work is needed to educate the research community about the individually randomized group treatment design and encourage publication of intraclass correlation coefficients to help inform future trial designs.

Advances in clinical trials methodology: Intervention optimization approaches in emergency medicine.

The classical two-arm randomized clinical trial (RCT) is designed to test the efficacy or effectiveness of an intervention, which may consist of one or more components. However, this approach does not enable the investigator to obtain information that is important in intervention development, such as which individual components of the intervention are efficacious, which are not and possibly should be removed, and whether any components interact. The Multiphase Optimization Strategy (MOST) is a new framework for development, optimization, and evaluation of interventions. MOST includes the RCT for purposes of evaluation, but inserts a phase of research before the RCT aimed at intervention optimization. The optimization phase requires one or more separate trials similar in scope to an RCT, but employing a different experimental design. The design of the optimization trial is selected strategically so as to maximize the amount of scientific information gained using the available resources. One consideration in selecting this experimental design is the type of intervention to be optimized. If a fixed intervention, i.e. one in which the same intervention content and intensity is provided to all participants, is to be optimized, a factorial experiment is often appropriate. If an adaptive intervention, i.e. one in which intervention content or intensity is varied in a principled manner, is to be optimized, a sequential multiple-assignment randomized trial (SMART) is often a good choice. The objective of this article is to describe MOST and the scientific rationale for its use; describe two current applications of MOST in emergency medicine research, one using a factorial experiment and the other using a SMART; and discuss funding strategies and potential future applications in studying the care of individuals with acute illness, injury, or behavioral disorders.

Health services access, utilization, and barriers for Arabic-speaking refugees resettled in Connecticut, USA.

BACKGROUND: Arabic-speaking refugees are the largest group of refugees arriving in the United States since 2008, yet little is known about their rates of healthcare access, utilization, and satisfaction after the end of the Refugee Medical Assistance (RMA) period. METHODS: This study was a cross-sectional observational study. From January to December 2019, a household survey was conducted of newly arrived Arabic-speaking refugees in Connecticut between 2016 and 2018. Households were interviewed in Arabic either in person or over the phone by one of five researchers. Descriptive statistics were generated for information collected on demographics, prevalence of chronic conditions, patterns of health seeking behavior, insurance status and patient satisfaction using the Patient Satisfaction Questionnaire (PSQ-18). RESULTS: Sixty-five households responded to the survey representing 295 Arabic-speaking refugees - of which 141 (48%) were children. Forty-seven households (72%) reported 142 chronic medical conditions among 295 individuals, 62 persons (21%) needed daily medication, 285 (97%) persons were insured. Median patient satisfaction was > 4.0 out of 5 for 6 of 7 domains of the PSQ-18 but wide variation (scores from 1.0 - 5.0). CONCLUSION: Arabic-speaking refugees in Connecticut participating in this study were young. The majority remained insured after their Refugee Medical Assistance lapsed. They expressed median high satisfaction with health services but with wide variation. Inaccessibility of health services in Arabic and difficulty obtaining medications remain areas in need of improvement.

Posttraumatic Stress Disorder, Antidepressant Use, and Hemorrhagic Stroke in Young Men and Women: A 13-Year Cohort Study.

BACKGROUND AND PURPOSE: Antidepressants are commonly prescribed for posttraumatic stress disorder (PTSD) and may increase the risk of bleeding, including hemorrhagic stroke. METHODS: We prospectively examined independent effects of PTSD, selective serotonin and norepinephrine reuptake inhibitors (SSRI and SNRI) on the risk of incident hemorrhagic stroke in a nationwide sample of 1.1 million young and middle-aged veterans. Time-varying multivariate Cox models were used to examine hemorrhagic stroke risk by PTSD status and use of SSRI or SNRI while adjusting for demographics, lifestyle factors, stroke, and psychiatric comorbidities. Sensitivity analyses controlled for health care utilization. RESULTS: During 13 years of follow-up (2.14 years on average), 507 patients (12% women) suffered a hemorrhagic stroke. The overall incidence rate was 1.70 events per 10 000-person years. In unadjusted models, PTSD was associated with an 82% greater risk of new-onset hemorrhagic stroke (hazard ratio [HR], 1.82 [95% CI, 1.48-2.24]), SSRI use was associated with a >2-fold risk (HR, 2.02 [95% CI, 1.66-2.57]), and SNRI use was associated with a 52% greater risk (HR, 1.52 [95% CI, 1.08-2.16]). In fully adjusted models, effects of PTSD and SNRI were attenuated (adjusted HR, 1.03 [95% CI, 0.81-1.34]; adjusted HR, 1.19 [95% CI, 0.83-1.71]), but SSRI use remained associated with a 45% greater risk of hemorrhagic stroke (adjusted HR, 1.45 [95% CI, 1.13-1.85]). Hypertension, drug abuse, and alcohol abuse were also associated with increased stroke risk. Nonobesity and being non-Hispanic were protective factors. In sensitivity analyses, health care utilization was a small but significant predictor of stroke. CONCLUSIONS: In the largest known investigation of PTSD and antidepressant-associated risk for hemorrhagic stroke in young adults, use of SSRIs, but neither PTSD nor SNRIs were independently associated with incident stroke. SNRIs may be preferable for treating PTSD and comorbid conditions, although pursuing other modifiable risk factors and non-pharmacological treatments for PTSD also remains essential.

Use of peripheral arterial tonometry in detection of abnormal coronary flow reserve.

BACKGROUND: We assessed the utility of EndoPAT, a device that measures reactive hyperemia index (RHI) as a clinical screening tool for identifying low coronary flow reserve (CFR). Distinguishing normal from low CFR aids assessment for coronary microvascular dysfunction (CMD) or large vessel coronary artery disease (CAD). METHODS: From June 2014-May 2019, in a convenience sample, we measured RHI in adults undergoing clinically indicated cardiac Rubidium-82 positron emission tomography/computed tomography (PET/CT) at a single center. Exclusion criteria were inability to consent, lack of English proficiency, and physical limitation. We defined low RHI as <1.67 and low CFR as <2.5. Distribution of RHI was skewed so we used its natural logarithm (LnRHI) to calculate Pearson correlation and area under the curve (AUC). RESULTS: Of 265 patients with PET/CT, we enrolled 131, and 100 had adequate data. Patients had a mean age of 61 years (SD = 12), 46% were female, 29% non-white. Thirty-six patients had low RHI, and 60 had depressed CFR. LnRHI did not distinguish patients with low from normal CFR (AUC = 0.53; 95% Cl, 0.41-0.64) and did not correlate with CFR (r = -0.021, p = 0.83). Low RHI did not distinguish patients with traditional CAD risk factors, presence of calcification, or perfusion defect (p > 0.05). Conversely, mean augmentation index, a measure of arterial stiffness, was higher with low RHI (p = 0.005) but not CFR (p = 0.625). RHI was lower in patients we identified as CMD (low CFR, no perfusion defect and calcium score of 0) (1.88 versus 2.21, p = 0.35) although we were underpowered (n = 12) to meet statistical significance. CONCLUSIONS: Peripheral RHI is insufficient as a clinical screening tool for low CFR as measured by cardiac PET/CT. Differences in vascular pathology assessed by each method may explain this finding.

Estimation of ascertainment bias and its effect on power in clinical trials with time-to-event outcomes.

While the gold standard for clinical trials is to blind all parties-participants, researchers, and evaluators-to treatment assignment, this is not always a possibility. When some or all of the above individuals know the treatment assignment, this leaves the study open to the introduction of postrandomization biases. In the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) trial, we were presented with the potential for the unblinded clinicians administering the treatment, as well as the individuals enrolled in the study, to introduce ascertainment bias into some but not all events comprising the primary outcome. In this article, we present ways to estimate the ascertainment bias for a time-to-event outcome, and discuss its impact on the overall power of a trial vs changing of the outcome definition to a more stringent unbiased definition that restricts attention to measurements less subject to potentially differential assessment. We found that for the majority of situations, it is better to revise the definition to a more stringent definition, as was done in STRIDE, even though fewer events may be observed.

A case study of ascertainment bias for the primary outcome in the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) trial.

BACKGROUND/AIM: In clinical trials, there is potential for bias from unblinded observers that may influence ascertainment of outcomes. This issue arose in the Strategies to Reduce Injuries and Develop Confidence in Elders trial, a cluster randomized trial to test a multicomponent intervention versus enhanced usual care (control) to prevent serious fall injuries, originally defined as a fall injury leading to medical attention. An unblinded nurse falls care manager administered the intervention, while the usual care arm did not involve contact with a falls care manager. Thus, there was an opportunity for falls care managers to refer participants reporting falls to seek medical attention. Since this type of observer bias could not occur in the usual care arm, there was potential for additional falls to be reported in the intervention arm, leading to dilution of the intervention effect and a reduction in study power. We describe the clinical basis for ascertainment bias, the statistical approach used to assess it, and its effect on study power. METHODS: The prespecified interim monitoring plan included a decision algorithm for assessing ascertainment bias and adapting (revising) the primary outcome definition, if necessary. The original definition categorized serious fall injuries requiring medical attention into Type 1 (fracture other than thoracic/lumbar vertebral, joint dislocation, cut requiring closure) and Type 2 (head injury, sprain or strain, bruising or swelling, other). The revised definition, proposed by the monitoring plan, excluded Type 2 injuries that did not necessarily require an overnight hospitalization since these would be most subject to bias. These injuries were categorized into those with (Type 2b) and without (Type 2c) medical attention. The remaining Type 2a injuries required medical attention and an overnight hospitalization. We used the ratio of 2b/(2b + 2c) in intervention versus control as a measure of ascertainment bias; ratios > 1 indicated the likelihood of falls care manager bias. We determined the effect of ascertainment bias on study power for the revised (Types 1 and 2a) versus original definition (Types 1, 2a, and 2b). RESULTS: The estimate of ascertainment bias was 1.14 (95% confidence interval: 0.98, 1.30), providing evidence of the likelihood of falls care manager bias. We estimated that this bias diluted the hazard ratio from the hypothesized 0.80 to 0.86 and reduced power to under 80% for the original primary outcome definition. In contrast, adapting the revised definition maintained study power at nearly 90%. CONCLUSION: There was evidence of ascertainment bias in the Strategies to Reduce Injuries and Develop Confidence in Elders trial. The decision to adapt the primary outcome definition reduced the likelihood of this bias while preserving the intervention effect and study power.

Incident Musculoskeletal Conditions Among Men and Women Veterans Returning From Deployment.

BACKGROUND: Military service confers an increased risk for musculoskeletal (MSK) injury among women and men Veterans. OBJECTIVE: The objective of this study was to determine the prevalence of MSK conditions at first visit to Veterans Affairs (VA), and the incidence rates of new MSK conditions in women and men Veterans with and without a baseline MSK condition. DESIGN: A cohort study including Veterans whose end of last deployment was between October 1, 2001 and October 1, 2015. SUBJECTS: A total of 765,465 Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn Veterans. MAIN OUTCOME MEASURES: Prevalent and incident MSK conditions identified through the International Classification of Diseases, ninth Revision, Clinical Modification diagnostic codes. RESULTS: Twenty-six percent of women and 29% of men present to the VA with a MSK condition. In those without an MSK diagnosis at baseline, the unadjusted rate of developing at least 1 MSK condition was 168 and 180 per 1000 person-year [hazard ratio (HR)=0.94; 95% confidence interval (CI)=0.92-0.95] in women and men. Women were more likely to develop newly diagnosed MSK conditions of the hip (HR=1.9; 95% CI=1.83-1.98) or the ankle/foot (HR=1.17; 95% CI=1.15-1.20) and less likely to develop MSK conditions of the upper extremity (HR=0.75; 95% CI=0.73-0.78), knee (HR=0.87; 95% CI=0.86-0.89), and spine (HR=0.94; 95% CI=0.93-0.96). In those with prevalent MSK conditions at baseline, the rate of developing a second MSK condition was higher in women than men (151 and 133/1000 person-year; HR=1.13; 95% CI=1.11-1.15). CONCLUSIONS: A high proportion of Veterans present to the VA with MSK conditions. Women are less likely to develop conditions related to the upper extremities, spine or knee, and more likely to have conditions of the hip or ankle/foot.

Validating Self-Reported Unhealthy Alcohol Use With Phosphatidylethanol (PEth) Among Patients With HIV.

BACKGROUND: We sought to compare self-reported alcohol consumption using Timeline Followback (TLFB) to biomarker-based evidence of significant alcohol use (phosphatidylethanol [PEth] > 20 ng/ml). Using data from patients with HIV (PWH) entering a clinical trial, we asked whether TLFB could predict PEth > 20 ng/ml and assessed the magnitude of association between TLFB and PEth level. METHODS: We defined unhealthy alcohol use as any alcohol use in the presence of liver disease, at-risk drinking, or alcohol use disorder. Self-reported alcohol use obtained from TLFB interview was assessed as mean number of drinks/day and number of heavy drinking days over the past 21 days. Dried blood spot samples for PEth were collected at the interview. We used logistic regression to predict PEth > 20 ng/ml and Spearman correlation to quantify the association with PEth, both as a function of TLFB. RESULTS: Among 282 individuals (99% men) in the analytic sample, approximately two-thirds (69%) of individuals had PEth > 20 ng/ml. The proportion with PEth > 20 ng/ml increased with increasing levels of self-reported alcohol use; of the 190 patients with either at-risk drinking or alcohol use disorder based on self-report, 82% had PEth > 20 ng/ml. Discrimination was better with number of drinks per day than heavy drinking days (AUC: 0.80 [95% CI: 0.74 to 0.85] vs. 0.74 [95% CI: 0.68 to 0.80]). The number of drinks per day and PEth were significantly and positively correlated across all levels of alcohol use (Spearman's R ranged from 0.29 to 0.56, all p values < 0.01). CONCLUSIONS: In this sample of PWH entering a clinical trial, mean numbers of drinks per day discriminated individuals with evidence of significant alcohol use by PEth. PEth complements self-report to improve identification of self-reported unhealthy alcohol use among PWH.

Exenatide extended release in patients with type 1 diabetes with and without residual insulin production.

AIMS: To test whether a long-acting GLP-1 receptor agonist would improve glucose control in patients with type 1 diabetes (T1D) and to determine whether the presence of residual beta cell function would affect the response. In addition, we sought to determine whether the drug would affect beta cell function. METHODS: We performed a randomized placebo-controlled trial of exenatide extended release (ER) in participants with T1D with and without detectable levels of C-peptide. Seventy-nine participants were randomized to exenatide ER 2 mcg weekly, or placebo, stratified by the presence or absence of detectable C-peptide levels. The primary outcome was the difference in glycated haemoglobin (HbA1c) levels at 24 weeks. Participants were followed for another 6 months off study drug. RESULTS: At week 24, the time of the primary outcome, the least squares (LS) mean HbA1c level was 7.76% (95% confidence interval [CI] 7.42, 8.10) in the exenatide ER group versus 8.0% (95% CI 7.64, 8.35) in the placebo group (P = 0.08). At week 12 the LS mean HbA1c levels were 7.71% (95% CI 7.37, 8.05) in the exenatide ER group versus 8.05% (95% CI 7.7, 8.4) in the placebo group (P = 0.01). The improvement at week 12 was driven mainly by those with detectable levels of C-peptide. Those treated with exenatide ER lost weight at 12 and 24 weeks compared to those treated with placebo (P <0.001 and P = 0.007). The total insulin dose was lower, but not when corrected for body weight, and was not affected by residual insulin production. Adverse events were more frequent with exenatide ER, but hypoglycaemia was not increased. CONCLUSION: Treatment with exenatide ER may have short-term benefits in some individuals with T1D who are overweight or who have detectable levels of C-peptide, but short-term improvements were not sustained.

Association of prescription opioids and incident cardiovascular risk factors among post-9/11 Veterans.

Reports indicate that long-term opioid therapy is associated with cardiovascular disease (CVD). Using VA electronic health record data, we measured the impact of opioid use on the incidence of modifiable CVD risk factors. We included Veterans whose encounter was between October 2001 to November 2014. We identified Veterans without CVD risk factors during our baseline period, defined as the date of first primary care visit plus 365 days. The main exposure was opioid prescriptions (yes/no, long-term (i.e. ≥90 days) vs no opioid, and long-term vs short-term (i.e. <90 days)), which was time-updated yearly from the end of the baseline period to February 2015. The main outcome measures were incident CVD risk factors (hypertension, dyslipidemia, diabetes, obesity, and current smoking). After excluding prevalent CVD risk factors, we identified 308,015 Veterans. During the first year of observation, 12,725 (4.1%) Veterans were prescribed opioids, including 2028 (0.6%) with long-term exposure. Compared to patients without opioid use, Veterans with opioid use were more likely to have CVD risk factors. Those with long-term exposure were at higher risk of having hypertension (adjusted average hazards ratio [HR] 1.45, 99% confidence interval [CI] 1.33-1.59), dyslipidemia (HR 1.45, 99% CI 1.35-156), diabetes (HR 1.30, 99% CI 1.07-1.57), current smoking status (HR 1.34, 99% CI 1.24-1.46), and obesity (HR 1.22, 99% CI 1.12-1.32). Compared to short-term exposure, long-term had higher risk of current smoking status (HR 1.12, 99% CI 1.01-1.24). These findings suggest potential benefit to screening and surveillance of CVD risk factors for patients prescribed opioids, especially long-term opioid therapy.