IMPORTANCE It remains unclear whether dabigatran etexilate mesylate is associated with higher risk of bleeding than warfarin sodium in real-world clinical practice. OBJECTIVE To compare the risk of bleeding associated with dabigatran and warfarin using Medicare data. DESIGN, SETTING, AND PARTICIPANTS In this retrospective cohort study, we used pharmacy and medical claims in 2010 to 2011 from a 5% random sample of Medicare beneficiaries. We identified participants as those newly diagnosed as having atrial fibrillation from October 1, 2010, through October 31, 2011, and who initiated dabigatran or warfarin treatment within 60 days of initial diagnosis. We followed up patients until discontinued use or switch of anticoagulants, death, or December 31, 2011. EXPOSURES Dabigatran users (n = 1302) and warfarin users (n = 8102). MAIN OUTCOMES AND MEASURES We identified any bleeding events and categorized them as major and minor bleeding by anatomical site. Major bleeding events included intracranial hemorrhage, hemoperitoneum, and inpatient or emergency department stays for hematuria, gastrointestinal, or other hemorrhage. We used a propensity score weighting mechanism to balance patient characteristics between 2 groups and Cox proportional hazards regression models to evaluate the risk of bleeding. We further examined the risk of bleeding for 4 subgroups of high-risk patients: those 75 years or older, African Americans, those with chronic kidney disease, and those with more than 7 concomitant comorbidities. RESULTS Dabigatran was associated with a higher risk of bleeding relative to warfarin, with hazard ratios of 1.30 (95% CI, 1.20-1.41) for any bleeding event, 1.58 (95% CI, 1.36-1.83) for major bleeding, and 1.85 (95% CI, 1.64-2.07) for gastrointestinal bleeding. The risk of intracranial hemorrhage was higher among warfarin users, with a hazard ratio of 0.32 (95% CI, 0.20-0.50) for dabigatran compared with warfarin. Dabigatran was consistently associated with an increased risk of major bleeding and gastrointestinal hemorrhage for all subgroups analyzed. The risk of major bleeding among dabigatran users was especially high for African Americans and patients with chronic kidney disease. CONCLUSIONS AND RELEVANCE Dabigatran was associated with a higher incidence of major bleeding (regardless of the anatomical site), a higher risk of gastrointestinal bleeding, but a lower risk of intracranial hemorrhage. Thus, dabigatran should be prescribed with caution, especially among high-risk patients.

IMPORTANCE Most studies that have examined drug prices have focused on list prices, without accounting for manufacturer rebates and other discounts, which have substantially increased in the last decade. OBJECTIVE To describe changes in list prices, net prices, and discounts for branded pharmaceutical products for which US sales are reported by publicly traded companies, and to determine the extent to which list price increases were offset by increases in discounts. DESIGN, SETTING, AND PARTICIPANTS Retrospective descriptive study using 2007-2018 pricing data from the investment firm SSR Health for branded products available before January 2007 with US sales reported by publicly traded companies (n = 602 drugs). Net prices were estimated by compiling company-reported sales for each product and number of units sold in the US. EXPOSURES Calendar year. MAIN OUTCOMES AND MEASURES Outcomes included list and net prices and discounts in Medicaid and other payers. List prices represent manufacturers' price to wholesalers or direct purchasers but do not account for discounts. Net prices represent revenue per unit of the product after all manufacturer concessions are accounted for (including rebates, coupon cards, and any other discount). Means of outcomes were calculated each year for the overall sample and 6 therapeutic classes, weighting each product by utilization and adjusting for inflation. RESULTS From 2007 to 2018, list prices increased by 159% (95% CI, 137%-181%), or 9.1% per year, while net prices increased by 60% (95% CI, 36%-84%), or 4.5% per year, with stable net prices between 2015 and 2018. Discounts increased from 40% to 76% in Medicaid and from 23% to 51% for other payers. Increases in discounts offset 62% of list price increases. There was large variability across classes. Multiple sclerosis treatments (n = 4) had the greatest increases in list (439%) and net (157%) prices. List prices of lipid-lowering agents (n = 11) increased by 278% and net prices by 95%. List prices of tumor necrosis factor inhibitors (n = 3) increased by 166% and net prices by 73%. List prices of insulins (n = 7) increased by 262%, and net prices by 51%. List prices of noninsulin antidiabetic agents (n = 10) increased by 165%, and net prices decreased by 1%. List price increases were lowest (59%) for antineoplastic agents (n = 44), but discounts only offset 41% of list price increases, leading to 35% increase in net prices. CONCLUSIONS AND RELEVANCE In this analysis of branded drugs in the US from 2007 to 2018, mean increases in list and net prices were substantial, although discounts offset an estimated 62% of list price increases with substantial variation across classes.

Key Points Question How does the risk of overdose change with the number of days with concurrent opioid and benzodiazepine use? Findings In this cohort study of US Medicare data, the overdose risk associated with concurrent benzodiazepine use changed over time. Concurrent benzodiazepine use was associated with a 5-fold increase in the risk of opioid-related overdose during the initial 90 days and an increase of 1.87 times on days 91 to 180. Meaning Policy interventions should focus on preventing concurrent opioid and benzodiazepine use in the first place instead of reducing the length of concurrent use. Patients using both medications should be closely monitored, particularly during the first days of concurrent use.

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Background Only 50% of atrial fibrillation ( AF ) patients recommended for oral anticoagulation ( OAC ) use these medications, and less than half of them adhere to OAC . In a cohort of Medicare beneficiaries newly diagnosed with AF , we identified groups of patients with similar trajectories of OAC use and adherence, and evaluated patient characteristics affecting group membership. Methods and Results We selected continuously enrolled Medicare Part D beneficiaries with first AF diagnosis in 2014 to 2015 (n=34 898). We calculated the proportion of days covered with OAC over the first 12 months after diagnosis and identified OAC adherence trajectories using group‐based trajectory models. We constructed multinomial logistic regression models to evaluate how demographics, system‐level factors, and clinical characteristics were associated with group membership. We identified 4 trajectories of OAC adherence: patients who never used OAC (43.8%), late OAC initiators (7.6%), early OAC discontinuers (8.9%), and continuously adherent patients (40.1%). Predictors such as sex, black race, residence in the South, or HAS ‐ BLED score were associated with not only OAC use, but also the timing of initiation and the likelihood of discontinuation. For example, HAS ‐ BLED score ≥4 was associated with a higher likelihood of not using OAC (odds ratio 1.35; 95% CI , 1.14–1.62), of late initiation (1.55; 95% CI , 1.11–2.05), and of early discontinuation (odds ratio 1.35; 95% CI , 1.01–1.84). Conclusions We identified 4 distinct trajectories of OAC adherence after first AF diagnosis, with <45% of newly diagnosed AF patients belonging to the trajectory group characterized by continuous OAC adherence. Trajectories were associated not only with demographic and clinical characteristics but also with regional factors.