Daylight Saving Time Practice and the Rate of Adverse Cardiovascular Events in the United States: A Probabilistic Assessment in a Large Nationwide Study.

We investigated the association of daylight saving time (DST) transitions with the rates of adverse cardiovascular events in a large, US-based nationwide study. The study cohort included 36,116,951 unique individuals from deidentified administrative claims data of the OptumLabs Data Warehouse. There were 74,722 total adverse cardiovascular events during DST transition and the control weeks (2 weeks before and after) in spring and autumn of 2015-2019. We used Bayesian hierarchical Poisson regression models to estimate event rate ratios representing the ratio of composite adverse cardiovascular event rates between DST transition and control weeks. There was an average increase of 3% (95% uncertainty interval, -3% to -10%) and 4% (95% uncertainty interval, -2% to -12%) in adverse cardiovascular event rates during Monday and Friday of the spring DST transition, respectively. The probability of this being associated with a moderate-to-large increase in the event rates (estimate event rate ratio, >1.10) was estimated to be less than 6% for Monday and Friday, and less than 1% for the remaining days. During autumn DST transition, the probability of any decrease in adverse cardiovascular event rates was estimated to be less than 46% and a moderate-to-large decrease in the event rates to be less than 4% across all days. Results were similar when adjusted by age. In conclusion, spring DST transition had a suggestive association with a minor increase in adverse cardiovascular event rates but with a very low estimated probability to be of clinical importance. Our findings suggest that DST transitions are unlikely to meaningfully impact the rate of cardiovascular events.

Clinical Trials Overview: From Explanatory to Pragmatic Clinical Trials.

Clinical trials have been the bedrock of research to evaluate the safety and efficacy of new medical, surgical, or other interventions. Traditional "explanatory" clinical trials have aimed to explain a biological cause (new treatment) and effect (patient outcome) while controlling for many factors that might impact the evaluation, such as restricted eligibility criteria, frequent follow-up visits, and multiple clinical and laboratory measures. Despite the benefits of a well-controlled clinical trial, compromises have been made that can limit who might benefit from a new intervention, can increase complexity of the conduct of a trial, or that lead to excessively long durations of trials. An alternative approach to evaluate the effectiveness of an intervention is based on "pragmatic" clinical trials, which consider how an intervention affects a patient's condition in the real world, accounting for how to optimize an intervention within the operations of busy and diverse clinical practices. Although we describe explanatory and pragmatic trial designs as separate approaches, there is a continuum of approaches that intersect. Some key points are the need to maintain scientific rigor, increase efficiency of clinical trials operations, ensure that trial results can be generalized to a broad spectrum of patients, and balance the needs of real-world clinical care. Pragmatic trials can leverage technology and telecommunication strategies of decentralized trials to further reach underrepresented and underserved patients to close the health disparity gaps.

Global morbidity and mortality of lower respiratory infections: A population -based study.

BACKGROUND: This study provides a comprehensive, comparative and updated estimates of temporal patterns of lower respiratory infections (LRIs) globally over the past three decades. METHODS: The data on morbidity and mortality of patients with LRIs at the global, regional and national levels were retrieved from the Global Burden of Disease (GBD) 2019 study. RESULTS: Globally, the incident cases of LRIs increased from 414,342,866 [95% uncertainty interval (UI):383,529,625 to 449, 086,938]in 1990 to 488,902,504(95% UI: 457,572,987 to 522,635,542)in 2019 with the age standardized incidence rate (ASIR) decreased from 8,276/100,000 persons (95% UI: 7,727 to 8,892) to 6,295/100,000 persons (95% UI: 5,887 to 6,737) between 1990 and 2019. Number of LRIs deaths were 2,493,200 (95% UI: 2,268,184 to 2,736,184) in 2019, a decrease of 24.9% (95% UI: -34.4 to -15.4) in the past 30 years. Meanwhile, the age-standardized death rate (ASDR) declined also from 67/100,000 persons (95% UI: 61 to 73) in 1990 to 34/100,000 persons (95% UI: 31 to 38) in 2019. Moreover, the numbers and age-standardized rates per 100,000 persons of morbidity and mortality varied widely by age, sex, Socio-Demographic Index (SDI) quintiles, and geographical locations in 2019. CONCLUSION: LRIs remain a major public health concern . Some differences in age, sex, SDI quintiles, and geographical locations contribute to LRIs-related global health policy development and health system resource optimization.

Cost Effectiveness of an Electrocardiographic Deep Learning Algorithm to Detect Asymptomatic Left Ventricular Dysfunction.

OBJECTIVE: To evaluate the cost-effectiveness of an artificial intelligence electrocardiogram (AI-ECG) algorithm under various clinical and cost scenarios when used for universal screening at age 65. PATIENTS AND METHODS: We used decision analytic modeling to perform a cost-effectiveness analysis of the use of AI-ECG to screen for asymptomatic left ventricular dysfunction (ALVD) once at age 65 compared with no screening. This screening consisted of an initial screening decision tree and subsequent construction of a Markov model. One-way sensitivity analysis on various disease and cost parameters to evaluate cost-effectiveness at both $50,000 per quality-adjusted life year (QALY) and $100,000 per QALY willingness-to-pay threshold. RESULTS: We found that for universal screening at age 65, the novel AI-ECG algorithm would cost $43,351 per QALY gained, test performance, disease characteristics, and testing cost parameters significantly affect cost-effectiveness, and screening at ages 55 and 75 would cost $48,649 and $52,072 per QALY gained, respectively. Overall, under most of the clinical scenarios modeled, coupled with its robust test performance in both testing and validation cohorts, screening with the novel AI-ECG algorithm appears to be cost-effective at a willingness-to-pay threshold of $50,000. CONCLUSION: Universal screening for ALVD with the novel AI-ECG appears to be cost-effective under most clinical scenarios with a cost of <$50,000 per QALY. Cost-effectiveness is particularly sensitive to both the probability of disease progression and the cost of screening and downstream testing. To improve cost-effectiveness modeling, further study of the natural progression and treatment of ALVD and external validation of AI-ECG should be undertaken.

Adoption of the Antifibrotic Medications Pirfenidone and Nintedanib for Patients with Idiopathic Pulmonary Fibrosis.

Rationale: In October 2014, the antifibrotic medications pirfenidone and nintedanib became the first medications approved by the U.S. Food and Drug Administration for use in patients with idiopathic pulmonary fibrosis (IPF). Since approval, there has been no nonregistry analysis of the real-world adoption of these medications in everyday clinical practice. Objectives: To evaluate the adoption, persistence, and out-of-pocket (OOP) costs of pirfenidone and nintedanib since their approval in the United States in 2014. Methods: A retrospective cohort analysis was performed by identifying privately insured and Medicare Advantage beneficiaries with IPF. We then split the patients into three cohorts: those who were untreated and those who filled a prescription for either pirfenidone or nintedanib between October 1, 2014, and July 31, 2019. The primary outcome was adoption of the medications. Secondary outcomes included medication persistence and prescription drug costs. Results: A total of 10,996 patients with IPF were identified in the data set. A minority of patients (26.4%) with IPF identified in the cohort had started either medication since approval in 2014, with the adoption of both medications being comparable at around 13.2%. Those receiving the medications were younger (72 vs. 73.9 yr; P < 0.0001) and healthier (3.9 vs. 4.9 comorbidities; P < 0.0001) than those not receiving treatment. Men were significantly more likely to receive treatment than woman (30.0% vs. 21.9%; P < 0.0001). Among treated patients, 42.8% discontinued the medications during the study period. Patients' OOP expenses per month were high for both drugs (mean, $397.51 for nintedanib; mean, $394.49 for pirfenidone). Conclusions: The adoption of both the antifibrotic medications in the United States in everyday practice has been low since approval and may be associated with the high OOP cost.

Assessment of Trends in Statin Therapy for Secondary Prevention of Atherosclerotic Cardiovascular Disease in US Adults From 2007 to 2016.

Importance: Atherosclerotic cardiovascular disease (ASCVD) is highly prevalent in the US, with studies indicating substantial rates of nonadherence to and undertreatment with statin therapy. The 2013 American College of Cardiology/American Heart Association guideline recommended high-intensity statins for all patients age 75 years and younger with documented ASCVD in whom such therapy is tolerated, but there is limited evidence documenting population trends of statin use, adherence, and outcomes in the periods before and after the update to the guideline. Objective: To assess trends in the use, adherence, cost, and outcomes of statin therapy for secondary prevention in patients with different types of ASCVD between 2007 and 2016. Design, Setting, and Participants: This retrospective cohort study used data from the OptumLab Data Warehouse database containing privately insured and Medicare Advantage enrollees with demographic characteristics similar to the national US population. Participants were adult patients (age ≥21 years) who had their first ASCVD event between January 1, 2007, and December 31, 2016. Data were characterized as belonging to 3 groups: (1) cardiovascular heart disease (CHD); (2) ischemic stroke or transient ischemic attack (TIA); and (3) peripheral artery disease (PAD). Data were analyzed from July 1 to August 1, 2018. Exposures: Calendar year of the initial ASCVD event. Main Outcomes and Measures: Trends in the statin use (within 30 days of discharge from hospitalization), adherence (proportion of days covered ≥80% within the first year), cost, major adverse cardiac events (1-year cumulative risk), and statin intolerance (within the first year). Results: Of the 284 954 patients with a new ASCVD event, 128 422 (45.1%) were women; the median age was 63 years (interquartile range [IQR], 54-72 years); 207 781 (72.9%) were White. The use of statins increased from 50.3% in 2007 to 59.9% in 2016, the use of high-intensity statins increased from 25.0% to 49.2%, and the adherence increased from 58.7% to 70.5% (P < .001 for all trends). Patients with CHD were more likely to receive statins and high-intensity statins and adhere to medications than patients with ischemic stroke, TIA, or PAD despite similar observed treatment benefit. In 2016, 80.9% of patients with CHD used a statin vs 65.8% of patients with ischemic stroke or TIA and 37.5% of patients with PAD. Out-of-pocket cost per 30-day decreased from a median of $20 (interquartile range, $7.6-$31.9) in 2007 to $2 (interquartile range, $1.6-$10.0) in 2016 (P < .001) with the increasing use of generic statins (42.0% in 2007 vs 94.9% in 2016; P < .001). Major adverse cardiac events decreased from 8.9% in 2007 to 6.5% in 2016 (P < .001) whereas statin intolerance increased from 4.0% to 5.1% (P < .001). Conclusions and Relevance: There have been modest improvements in the use, adherence, and cardiovascular outcomes over the past decade for statin therapy in patients with ASCVD, but a substantial and persistent treatment gap exists between patients with and without CHD, between men and women.

Comparative Effectiveness of Generic vs Brand-Name Levothyroxine in Achieving Normal Thyrotropin Levels.

Importance: Whether the use of generic vs brand levothyroxine affects thyrotropin levels remains unclear. Objective: To compare the effectiveness of generic vs brand levothyroxine in achieving and maintaining normal thyrotropin levels among new users. Design, Setting, and Participants: This retrospective, 1:1 propensity score-matched longitudinal cohort study used the OptumLabs Data Warehouse administrative claims database linked to laboratory results from commercially insured and Medicare Advantage enrollees throughout the United States. Eligible patients were adults (aged ≥18 years) with thyrotropin levels ranging from 4.5 to 19.9 mIU/L who initiated use of generic or brand-name levothyroxine from January 1, 2008, to October 1, 2017. Data were analyzed from August 13, 2018, to October 25, 2019. Exposure: Patients received generic or brand-name levothyroxine. Main Outcomes and Measures: Proportion of patients with normal vs markedly abnormal thyrotropin levels (<0.1 or >10 mIU/L) within 3 months and with stable thyrotropin levels within 3 months after the thyrotropin value fell into the normal range. Results: A total of 17 598 patients were included (69.0% female; 74.0% White; mean [SD] age, 55.1 [16.0] years), of whom 15 299 filled generic and 2299 filled brand-name levothyroxine prescriptions during the study period. Among 4570 propensity score-matched patients (mean [SD] age, 50.3 [13.8] years; 3457 [75.6%] female; 3510 [76.8%] White), the proportion with normal thyrotropin levels within 3 months of filling levothyroxine prescriptions was similar for patients who received generic vs brand-name levothyroxine (1722 [75.4%; 95% CI, 71.9%-79.0%] vs 1757 [76.9%; 95% CI, 73.4%-80.6%]; P = .23), as was the proportion with markedly abnormal levels (94 [4.1%; 95% CI, 3.4%-5.0%] vs 88 [3.9%; 95% CI, 3.1%-4.7%]; P = .65). Among 1034 propensity score-matched patients who achieved a normal thyrotropin value within 3 months of initiation of levothyroxine, the proportion maintaining subsequent normal thyrotropin levels during the next 3 months was similar for patients receiving generic vs brand-name levothyroxine (427 [82.6%] vs 433 [83.8%]; P = .62). Conclusions and Relevance: Initiation of generic vs brand-name levothyroxine formulations was associated with similar rates of normal and stable thyrotropin levels. These results suggest that generic levothyroxine as initial therapy for mild thyroid dysfunction is as effective as brand-name levothyroxine.

Assessing and Mitigating Bias in Medical Artificial Intelligence: The Effects of Race and Ethnicity on a Deep Learning Model for ECG Analysis.

BACKGROUND: Deep learning algorithms derived in homogeneous populations may be poorly generalizable and have the potential to reflect, perpetuate, and even exacerbate racial/ethnic disparities in health and health care. In this study, we aimed to (1) assess whether the performance of a deep learning algorithm designed to detect low left ventricular ejection fraction using the 12-lead ECG varies by race/ethnicity and to (2) determine whether its performance is determined by the derivation population or by racial variation in the ECG. METHODS: We performed a retrospective cohort analysis that included 97 829 patients with paired ECGs and echocardiograms. We tested the model performance by race/ethnicity for convolutional neural network designed to identify patients with a left ventricular ejection fraction ≤35% from the 12-lead ECG. RESULTS: The convolutional neural network that was previously derived in a homogeneous population (derivation cohort, n=44 959; 96.2% non-Hispanic white) demonstrated consistent performance to detect low left ventricular ejection fraction across a range of racial/ethnic subgroups in a separate testing cohort (n=52 870): non-Hispanic white (n=44 524; area under the curve [AUC], 0.931), Asian (n=557; AUC, 0.961), black/African American (n=651; AUC, 0.937), Hispanic/Latino (n=331; AUC, 0.937), and American Indian/Native Alaskan (n=223; AUC, 0.938). In secondary analyses, a separate neural network was able to discern racial subgroup category (black/African American [AUC, 0.84], and white, non-Hispanic [AUC, 0.76] in a 5-class classifier), and a network trained only in non-Hispanic whites from the original derivation cohort performed similarly well across a range of racial/ethnic subgroups in the testing cohort with an AUC of at least 0.930 in all racial/ethnic subgroups. CONCLUSIONS: Our study demonstrates that while ECG characteristics vary by race, this did not impact the ability of a convolutional neural network to predict low left ventricular ejection fraction from the ECG. We recommend reporting of performance among diverse ethnic, racial, age, and sex groups for all new artificial intelligence tools to ensure responsible use of artificial intelligence in medicine.

Assessment of Endovascular Treatment for Acute Basilar Artery Occlusion via a Nationwide Prospective Registry.

Importance: Several randomized clinical trials have recently established the safety and efficacy of endovascular treatment (EVT) of acute ischemic stroke in the anterior circulation. However, it remains uncertain whether patients with acute basilar artery occlusion (BAO) benefit from EVT. Objective: To evaluate the association between EVT and clinical outcomes of patients with acute BAO. Design, Setting, and Participants: This nonrandomized cohort study, the EVT for Acute Basilar Artery Occlusion Study (BASILAR) study, was a nationwide prospective registry of consecutive patients presenting with an acute, symptomatic, radiologically confirmed BAO to 47 comprehensive stroke centers across 15 provinces in China between January 2014 and May 2019. Patients with acute BAO within 24 hours of estimated occlusion time were divided into groups receiving standard medical treatment plus EVT or standard medical treatment alone. Main Outcomes and Measures: The primary outcome was the improvement in modified Rankin Scale scores (range, 0 to 6 points, with higher scores indicating greater disability) at 90 days across the 2 groups assessed as a common odds ratio using ordinal logistic regression shift analysis, adjusted for prespecified prognostic factors. The secondary efficacy outcome was the rate of favorable functional outcomes defined as modified Rankin Scale scores of 3 or less (indicating an ability to walk unassisted) at 90 days. Safety outcomes included symptomatic intracerebral hemorrhage and 90-day mortality. Results: A total of 1254 patients were assessed, and 829 patients (of whom 612 were men [73.8%]; median [interquartile] age, 65 [57-74] years) were recruited into the study. Of these, 647 were treated with standard medical treatment plus EVT and 182 with standard medical treatment alone. Ninety-day functional outcomes were substantially improved by EVT (adjusted common odds ratio, 3.08 [95% CI, 2.09-4.55]; P < .001). Moreover, EVT was associated with a significantly higher rate of 90-day modified Rankin Scale scores of 3 or less (adjusted odds ratio, 4.70 [95% CI, 2.53-8.75]; P < .001) and a lower rate of 90-day mortality (adjusted odds ratio, 2.93 [95% CI, 1.95-4.40]; P < .001) despite an increase in symptomatic intracerebral hemorrhage (45 of 636 patients [7.1%] vs 1 of 182 patients [0.5%]; P < .001). Conclusions and Relevance: Among patients with acute BAO, EVT administered within 24 hours of estimated occlusion time is associated with better functional outcomes and reduced mortality.

ECG AI-Guided Screening for Low Ejection Fraction (EAGLE): Rationale and design of a pragmatic cluster randomized trial.

BACKGROUND: A deep learning algorithm to detect low ejection fraction (EF) using routine 12-lead electrocardiogram (ECG) has recently been developed and validated. The algorithm was incorporated into the electronic health record (EHR) to automatically screen for low EF, encouraging clinicians to obtain a confirmatory transthoracic echocardiogram (TTE) for previously undiagnosed patients, thereby facilitating early diagnosis and treatment. OBJECTIVES: To prospectively evaluate a novel artificial intelligence (AI) screening tool for detecting low EF in primary care practices. DESIGN: The EAGLE trial is a pragmatic two-arm cluster randomized trial (NCT04000087) that will randomize >100 clinical teams (i.e., clusters) to either intervention (access to the new AI screening tool) or control (usual care) at 48 primary care practices across Minnesota and Wisconsin. The trial is expected to involve approximately 400 clinicians and 20,000 patients. The primary endpoint is newly discovered EF ≤50%. Eligible patients will include adults who undergo ECG for any reason and have not been previously diagnosed with low EF. Data will be pulled from the EHR, and no contact will be made with patients. A positive deviance qualitative study and a post-implementation survey will be conducted among select clinicians to identify facilitators and barriers to using the new screening report. SUMMARY: This trial will examine the effectiveness of the AI-enabled ECG for detection of asymptomatic low EF in routine primary care practices and will be among the first to prospectively evaluate the value of AI in real-world practice. Its findings will inform future implementation strategies for the translation of other AI-enabled algorithms.

Risk of Gastrointestinal Bleeding Increases With Combinations of Antithrombotic Agents and Patient Age.

BACKGROUND & AIMS: The safety of different antithrombotic strategies for patients with 1 or more indication for antithrombotic drugs has not been determined. We investigated the risk and time frame for gastrointestinal bleeding (GIB) in patients prescribed different antithrombotic regimens. We proposed that risk would increase over time and with combination regimens, especially among elderly patients. METHODS: We performed a retrospective analysis of nationwide claims data from privately insured and Medicare Advantage enrollees who received anticoagulant and/or antiplatelet agents from October 1, 2010, through May 31, 2017. Patients were stratified by their prescriptions (anticoagulant alone, antiplatelet alone, or a combination) and by their primary diagnosis (atrial fibrillation, ischemic heart disease, or venous thromboembolism). The 1-year GIB risk was estimated using parametric time-to-event survival models and expressed as annualized risk and number needed to harm (NNH). RESULTS: Our final analysis included 311,211 patients (mean ages, 67 years for monotherapy and 69.8 years for combination antithrombotic therapy). There was no significant difference in the proportion of patients with bleeding after anticoagulant or antiplatelet monotherapy (∼3.5%/year). Combination antithrombotic therapy increased GIB risk compared with anticoagulant (NNH, 29) or antiplatelet (NNH, 31) monotherapy, regardless of the patients' diagnosis or time point analyzed. Advancing age was associated with increasing 1-year probability of GIB. Patients prescribed combination therapy were at the greatest risk for GIB, especially after the age of 75 years (GIB occurred in 10%-17.5% of patients/y). CONCLUSIONS: In an analysis of nationwide insurance and Medicare claims data, we found GIB to occur in a higher proportion of patients prescribed combinations of anticoagulant and antiplatelet agents compared with monotherapy. Among all drug exposure categories and cardiovascular conditions, the risk of GIB increased with age, especially among patients older than 75 years.

Evolution of the American College of Cardiology and American Heart Association Cardiology Clinical Practice Guidelines: A 10-Year Assessment.

Background The American College of Cardiology and American Heart Association periodically revise clinical practice guidelines. We evaluated changes in the evidence underlying guidelines published over a 10-year period. Methods and Results Thirty-five American College of Cardiology/American Heart Association guidelines were divided into 2 time periods: 2008 to 2012 and 2013 to 2017. Guidelines were categorized into the following topic areas: arrhythmias, prevention, acute and stable ischemia, heart failure, valvular heart disease, and vascular medicine. Changes in recommendations were assessed for each topic area. American College of Cardiology/American Heart Association designated class of recommendation as level I, II, or III (I represented "strongly recommended") and levels of evidence (LOE) as A, C, or C (A represented "highest quality"). The median number of recommendations per each topic area was 281 (198-536, interquartile range) in 2008 to 2012 versus 247 (190-451.3, interquartile range) in 2013 to 2017. The median proportion of class of recommendation I was 49.3% and 44.4% in the 2 time periods, 38.0% and 44.5% for class of recommendation II, and 12.5% and 11.2% for class of recommendation III. Median proportions for LOE A were 15.7% and 14.1%, 41.0% and 52.8% for LOE B, and 46.9% and 32.5% for LOE C. The decrease in the proportion of LOE C was highest in heart failure (24.8%), valvular heart disease (22.3%), and arrhythmia (19.2%). An increase in the proportion of LOE B was observed for these same areas: 31.8%, 23.8%, and 19.2%, respectively. Conclusions There has been a decrease in American College of Cardiology/American Heart Association guidelines recommendations, driven by removal of recommendations based on lower quality of evidence, although there was no corresponding increase in the highest quality of evidence.

Variation in Treatment Practices for Subclinical Hypothyroidism in Pregnancy: US National Assessment.

CONTEXT: Although thyroid hormone replacement may improve outcomes in pregnant women with subclinical hypothyroidism (SCH), the extent to which they receive treatment is unknown. OBJECTIVE: To describe levothyroxine (LT4) treatment practices for pregnant women with SCH. DESIGN: Retrospective cohort study. SETTING: Large US administrative claims database. PARTICIPANTS: Pregnant women with SCH defined by untreated TSH 2.5 to 10 mIU/L. MAIN OUTCOME MEASURE: Initiation of LT4 as a function of treating clinician specialty (endocrinology, obstetrics/gynecology, primary care, or other), baseline TSH, patient clinical and demographic factors, and US region. RESULTS: We identified 7990 pregnant women with SCH; only 1214 (15.2%) received LT4. Treatment was more likely in patients with higher TSH, obesity, recurrent pregnancy loss, thyroid disease, and cared for by endocrinologists. Proportion of treated women increased over time; LT4 treatment was twice as likely in 2014 as in 2010. Women in Northeast and West US were more likely to receive LT4 compared with other regions. Asian women were more likely, whereas Hispanic women were less likely, to receive LT4 compared with white women. Endocrinologists started LT4 at lower TSH thresholds than other specialties, and treated women who were more likely to have had recurrent pregnancy loss and thyroid disease than women treated by other clinicians. CONCLUSIONS: We found large variation in the prescription of LT4 to pregnant women with SCH, although most treatment-eligible women remained untreated. Therapy initiation is associated with geographic, clinician, and patient characteristics. This evidence can inform quality improvement efforts to optimize care for pregnant women with SCH.

Generic and Brand-Name Thyroid Hormone Drug Use Among Commercially Insured and Medicare Beneficiaries, 2007 Through 2016.

CONTEXT: Generic drugs account for 9 out of 10 prescriptions dispensed in the United States but for a lower proportion of commonly prescribed thyroid hormone replacement therapies. OBJECTIVE: Characterize temporal patterns of generic and brand-name thyroid hormone drug use, including patient and prescriber characteristics associated with brand-name use. DESIGN AND SETTING: Cross-sectional longitudinal analysis of national data from a large administrative claims database from January 2007 through December 2016. PATIENTS: Adults with insurance coverage through commercial, Medicare Advantage, and Medicare Part D health plans. MAIN OUTCOME MEASURES: Generic and brand-name thyroid hormone drug use. RESULTS: From 2007 to 2016, the annual number of thyroid hormone treatment pharmacy fills increased from 8,905,836 in 2007 to 11,613,923 in 2016, 73.6% of which were for generic levothyroxine, 23.4% for brand-name levothyroxine, and the remaining for other formulations. Dispensing of generic thyroid hormone drugs increased from 59.8% in 2007 to 84.9% in 2016 and was consistently higher among Medicare Advantage and Medicare Part D when compared with the commercial beneficiary population. For all three beneficiary populations, use of brand-name products was less common among older adults and more common among women and those receiving prescriptions from endocrinologists and was more common among those of white race and with greater household income for the Medicare Advantage and commercial beneficiary populations (P < 0.001). CONCLUSIONS: Brand-name thyroid hormone product use declined from 2007 to 2016 among three large, national insurer beneficiary populations. Although certain patient characteristics were associated with brand-name use, prescriber specialty was the strongest predictor.

Outcomes Associated With Apixaban Use in Patients With End-Stage Kidney Disease and Atrial Fibrillation in the United States.

BACKGROUND: Patients with end-stage kidney disease (ESKD) on dialysis were excluded from clinical trials of direct oral anticoagulants for atrial fibrillation (AF). Recent data have raised concerns regarding the safety of dabigatran and rivaroxaban, but apixaban has not been evaluated despite current labeling supporting its use in this population. The goal of this study was to determine patterns of apixaban use and its associated outcomes in dialysis-dependent patients with ESKD and AF. METHODS: We performed a retrospective cohort study of Medicare beneficiaries included in the United States Renal Data System (October 2010 to December 2015). Eligible patients were those with ESKD and AF undergoing dialysis who initiated treatment with an oral anticoagulant. Because of the small number of dabigatran and rivaroxaban users, outcomes were only assessed in patients treated with apixaban or warfarin. Apixaban and warfarin patients were matched (1:3) based on prognostic score. Differences between groups in survival free of stroke or systemic embolism, major bleeding, gastrointestinal bleeding, intracranial bleeding, and death were assessed using Kaplan-Meier analyses. Hazard ratios (HRs) and 95% CIs were derived from Cox regression analyses. RESULTS: The study population consisted of 25 523 patients (45.7% women; 68.2±11.9 years of age), including 2351 patients on apixaban and 23 172 patients on warfarin. An annual increase in apixaban prescriptions was observed after its marketing approval at the end of 2012, such that 26.6% of new anticoagulant prescriptions in 2015 were for apixaban. In matched cohorts, there was no difference in the risks of stroke/systemic embolism between apixaban and warfarin (HR, 0.88; 95% CI, 0.69-1.12; P=0.29), but apixaban was associated with a significantly lower risk of major bleeding (HR, 0.72; 95% CI, 0.59-0.87; P<0.001). In sensitivity analyses, standard-dose apixaban (5 mg twice a day; n=1034) was associated with significantly lower risks of stroke/systemic embolism and death as compared with either reduced-dose apixaban (2.5 mg twice a day; n=1317; HR, 0.61; 95% CI, 0.37-0.98; P=0.04 for stroke/systemic embolism; HR, 0.64; 95% CI, 0.45-0.92; P=0.01 for death) or warfarin (HR, 0.64; 95% CI, 0.42-0.97; P=0.04 for stroke/systemic embolism; HR, 0.63; 95% CI, 0.46-0.85; P=0.003 for death). CONCLUSIONS: Among patients with ESKD and AF on dialysis, apixaban use may be associated with a lower risk of major bleeding compared with warfarin, with a standard 5 mg twice a day dose also associated with reductions in thromboembolic and mortality risk.

Adoption of Sacubitril/Valsartan for the Management of Patients With Heart Failure.

BACKGROUND: The US Food and Drug Administration approved the use of sacubitril/valsartan in patients with heart failure with reduced ejection fraction in July 2015. We aimed to assess the adoption and prescription drug costs of sacubitril/valsartan in its first 18 months after Food and Drug Administration approval. METHODS AND RESULTS: Using a large US insurance database, we identified privately insured and Medicare Advantage beneficiaries who filled a first prescription for sacubitril/valsartan between July 1, 2015, and December 31, 2016. We compared them to patients treated with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Outcomes included adoption, prescription drug costs, and 180-day adherence, defined as a proportion of days covered ≥80%. A total of 2244 patients initiated sacubitril/valsartan. Although the number of users increased over time, the proportion of heart failure with reduced ejection fraction patients taking sacubitril/valsartan remained low (<3%). Patients prescribed sacubitril/valsartan were younger, more often male, with less comorbidity than those taking an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker. Although a majority of prescription costs were covered by the health plan (mean, $328.37; median, $362.44 per 30-day prescription), out-of-pocket costs were still high (mean, $71.16; median, $40.27). By comparison, median out-of-pocket costs were $2 to $3 for lisinopril, losartan, carvedilol, and spironolactone. Overall, 59.1% of patients were adherent to sacubitril/valsartan. Refill patterns suggested that nearly half of nonadherent patients discontinued sacubitril/valsartan within 180 days of starting. CONCLUSIONS: Adoption of sacubitril/valsartan after Food and Drug Administration approval has been slow and may be associated with the high cost.

Comparative Effectiveness of Uterine Leiomyoma Procedures Using a Large Insurance Claims Database.

OBJECTIVE: To compare risk of reintervention, long-term clinical outcomes, and health care utilization among women who have bulk symptoms from leiomyoma and who underwent the following procedures: hysterectomy, myomectomy, uterine artery embolization, and magnetic resonance-guided, focused ultrasound surgery. METHODS: This was a retrospective analysis of administrative claims from a large U.S. commercial insurance database. Women aged 18-54 years undergoing any of the previously mentioned leiomyoma procedures between 2000 and 2013 were included. We assessed the following outcome measures: risk of reintervention between uterine-sparing procedures, risk of other surgical procedures or complications of the index procedure, 5-year health care utilization, pregnancy rates, and reproductive outcomes. Propensity score matching along with Cox proportional hazard models were used to adjust for differences in baseline characteristics between study cohorts. RESULTS: Among the 135,522 study-eligible women with mean follow-up of 3.4 years, hysterectomy was the most common first-line procedural therapy (111,324 [82.2%]) followed by myomectomy (19,965 [14.7%]), uterine artery embolization (4,186 [3.1%]) and magnetic resonance-guided focused ultrasound surgery (47 [0.0003%]). Small but statistically significant differences were noted for uterine artery embolization and myomectomy in reintervention rate (17.1% compared with 15.0%, P=.02), subsequent hysterectomy rates (13.2% compared with 11.1%, P<.01) and subsequent complications from index procedures (18.1% compared with 24.6%, P<.001). During follow-up, women undergoing myomectomy had lower leiomyoma-related health care utilization, but had higher all-cause outpatient services. Pregnancy rates were 7.5% and 2.2% among myomectomy and uterine artery embolization cohorts, respectively (P<.001) with both cohorts having similar rates of adverse reproductive outcome (69.4%). CONCLUSIONS: Although the overwhelming majority of women having leiomyoma with bulk symptoms underwent hysterectomy as their first treatment procedure, among those undergoing uterine-sparing index procedures, approximately one seventh had a reintervention, and one tenth ended up undergoing hysterectomy during follow-up. Compared with women undergoing myomectomy, women undergoing uterine artery embolization had a higher risk of reintervention, lower risk of subsequent complications, but similar rate of adverse reproductive outcomes.

Thyroid hormone treatment among pregnant women with subclinical hypothyroidism: US national assessment.

OBJECTIVE:  To estimate the effectiveness and safety of thyroid hormone treatment among pregnant women with subclinical hypothyroidism. DESIGN:  Retrospective cohort study. SETTING:  Large US administrative database between 1 January 2010 and 31 December 2014. PARTICIPANTS:  5405 pregnant women with subclinical hypothyroidism, defined as untreated thyroid stimulating hormone (TSH) concentration 2.5-10 mIU/L. EXPOSURE:  Thyroid hormone therapy. MAIN OUTCOME MEASURE:  Pregnancy loss and other pre-specified maternal and fetal pregnancy related adverse outcomes. RESULTS:  Among 5405 pregnant women with subclinical hypothyroidism, 843 with a mean pre-treatment TSH concentration of 4.8 (SD 1.7) mIU/L were treated with thyroid hormone and 4562 with a mean baseline TSH concentration of 3.3 (SD 0.9) mIU/L were not treated (P<0.01). Pregnancy loss was significantly less common among treated women (n=89; 10.6%) than among untreated women (n=614; 13.5%) (P<0.01). Compared with the untreated group, treated women had lower adjusted odds of pregnancy loss (odds ratio 0.62, 95% confidence interval 0.48 to 0.82) but higher odds of preterm delivery (1.60, 1.14 to 2.24), gestational diabetes (1.37, 1.05 to 1.79), and pre-eclampsia (1.61, 1.10 to 2.37); other pregnancy related adverse outcomes were similar between the two groups. The adjusted odds of pregnancy loss were lower in treated women than in untreated women if their pre-treatment TSH concentration was 4.1-10 mIU/L (odds ratio 0.45, 0.30 to 0.65) but not if it was 2.5-4.0 mIU/L (0.91, 0.65 to 1.23) (P<0.01). CONCLUSION:  Thyroid hormone treatment was associated with decreased risk of pregnancy loss among women with subclinical hypothyroidism, especially those with pre-treatment TSH concentrations of 4.1-10 mIU/L. However, the increased risk of other pregnancy related adverse outcomes calls for additional studies evaluating the safety of thyroid hormone treatment in this patient population.