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Purpose To compare risks of interstitial lung disease (ILD) between patients treated with dronedarone versus other antiarrhythmics. Methods Parallel retrospective cohort studies were conducted in the United States Department of Defense Military Health System database (DoD) and the HealthCore Integrated Research Database (HIRD). Study patients were treated for atrial fibrillation (AF) with dronedarone, amiodarone, sotalol, or flecainide. Propensity score matching was employed to create analysis cohorts balanced on baseline variables considered potential confounders of treatment decisions. The study period of July 20, 2008 through September 30, 2014 included a 1‐year baseline and minimum 6 months of follow‐up, for patients with drugs dispensed between July 20, 2009 and March 31, 2014. Suspect ILD outcomes were reviewed by independent adjudicators. Cox proportional hazards regression compared risk of confirmed ILD between dronedarone and each comparator cohort. A sensitivity analysis examined the effect of broadening the outcome definition. Results A total 72 ILD cases (52 DoD; 20 HIRD) were confirmed among 27 892 patients. ILD risk was significantly higher among amiodarone than dronedarone initiators in DoD (HR = 2.5; 95% CI = 1.1–5.3, p = 0.02). No difference was detected in HIRD (HR = 1.0; 95% CI = 0.4–2.4). Corresponding risks in sotalol and flecainide exposure groups did not differ significantly from dronedarone in either database. Conclusions ILD risk among AF patients initiated on dronedarone therapy was comparable to or lower than that of amiodarone initiators, and similar to that of new sotalol or flecainide users. This finding suggests that elevated ILD risk associated with amiodarone does not necessarily extend to dronedarone or other antiarrhythmic drugs.

Real-world data are a well-recognized component within the drug lifecycle, and such data are generated from a range of sources and study designs, including claims databases, electronic health records, non-interventional studies (NIS) and registries. While this information can be of vital clinical importance, there may be challenges in understanding the relevance of the differing study designs, endpoints and populations. Here, we summarize the value of real-world evidence and considerations pertinent to their use in clinical research. Owing to the variety of analyses being conducted using real-world data, it is important for researchers and clinicians to have a clear understanding of the nature and origin of those data, and to ensure they are valid, reliable and robust in terms of extrapolating meaningful findings. There are crucial questions to address when evaluating real-world studies, and we introduce a checklist to meet these objectives. In addition to advice for appraising data quality and study designs, several updates will be covered from real-world studies of rivaroxaban for stroke prevention in patients with atrial fibrillation (AF): the nationwide Danish cohort study, U.S. Department of Defense Military Health System database, retrospective claim database study REAFFIRM and a pooled analysis from the global NIS XArelto on preveNtion of sTroke and non-central nervoUS system systemic embolism in patients with non-valvular atrial fibrillation (XANTUS). Real-world studies consistently show that rivaroxaban is an effective treatment option with acceptable safety when used for stroke prevention in a large number of patients with AF across the globe.

Rivaroxaban is a novel oral anticoagulant indicated for prophylaxis against deep vein thrombosis and pulmonary embolism in patients undergoing total hip replacement (THR) or total knee replacement (TKR) surgery.To evaluate major bleeding (MB) in THR/TKR patients receiving post-operative rivaroxaban.Electronic medical records of nearly 10 million US Department of Defense (DoD) beneficiaries were queried from 1 January 2013 through 30 June 2015. Using the validated Cunningham case-finding algorithm, post-surgical MB events in rivaroxaban users were identified and analyzed. The incidence of MB was determined, and descriptive statistics were used to compare patient characteristics and other covariates in those with and without MB. Two additional methods were used to explore and identify bleeding cases that were not considered MB events per the study case-finding algorithm.A total of 12,429 patients received THR and/or TKR surgery, and were post-operatively prescribed rivaroxaban. Nine patients had MB, yielding an incidence proportion of 0.07% (95% CI 0.02-0.13). The alternative case-finding methods found bleeding incidences of 0.46% and 0.21%, though it is not clear whether these are clinical MB cases, since the alternative methods were not validated.The incidence of MB in this retrospective analysis is lower than that observed in the clinical trials of rivaroxaban. Whether this is due to lower real-world MB rates or challenges with case-finding algorithms is unclear.

Background In nonvalvular atrial fibrillation (NVAF), rivaroxaban is used to prevent stroke and systemic embolism. Objective To evaluate major bleeding (MB) in NVAF patients treated with rivaroxaban in a real-world clinical setting. Methods From January 1, 2013, to March 31, 2014, US Department of Defense electronic health care records were queried to describe MB rates and demographics. Major bleeding was identified using a validated algorithm. Results Of 27 467 patients receiving rivaroxaban, 496 MB events occurred in 478 patients, an incidence of 2.86 per 100 person-years (95% confidence interval: 2.61-3.13). The MB patients were older, mean (SD) age of 78.4 (7.7) vs 75.7 (9.7) years, compared with non-MB patients. Patients with MB had higher rates of hypertension (95.6% vs 75.8%), coronary artery disease (64.2% vs 36.7%), heart failure (48.5% vs 23.7%), and renal disease (38.7% vs 16.7%). Of MB patients, 63.2% were taking 20 mg, 32.2% 15 mg, and 4.6% 10 mg of rivaroxaban. Four percent of MB patients took warfarin within the prior 30 days. Major bleeding was most commonly gastrointestinal (88.5%) or intracranial (7.5%). Although 46.7% of MB patients received a transfusion, none had sufficient evidence of receiving any type of clotting factor. Fourteen died during their MB hospitalization, yielding a fatal bleeding incidence rate of 0.08 per 100 person-years (95% confidence interval: 0.05-0.14). Mean age at death was 82.4 years. Conclusions In this large observational study, the MB rate was generally consistent with the registration trial results, and fatal bleeds were rare.

A previously healthy 48-year-old active duty man, who had been treated for an elbow abscess 3 weeks earlier, presented to an emergency department in Bahrain with tachycardia, pericardial friction rub and jugular venous distention. Cardiac tamponade was confirmed on transthoracic echocardiogram and he was taken for emergent pericardiocentesis. Pericardial fluid cultures grew community-acquired methicillin-resistant Staphylococcus aureus . Despite ongoing treatment with intravenous vancomycin, he developed a recurrent fibrinous pericardial effusion and constrictive pericarditis requiring pericardiectomy. Though he initially did well postoperatively, he developed drug reaction with eosinophilia and systemic symptoms syndrome in response to vancomycin. He was transitioned to ceftaroline and started on high-dose steroids. He recovered during a week-long admission and was discharged home. Several weeks later at follow-up he was doing well and had resumed moderate intensity exercise.

Introduction: Rivaroxaban, a direct factor Xa inhibitor approved in 2011, reduces the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF). Phase 3 results from the registration trial showed a major bleeding (MB) rate of 3.6 per 100 person-years. Objective: To evaluate MB incidence among NVAF patients taking rivaroxaban in a post-approval clinical setting. Methods: From January 1, 2013 to June 30, 2016, over 10 million electronic medical records from the Department of Defense Military Health System were queried. A validated MB case-finding algorithm (Cunningham) was used to identify MB-related hospitalizations. Major bleeding incidence, patient characteristics, comorbid conditions, concomitant medications, bleeding management, and fatal bleeds were assessed. Results: Of 57,070 rivaroxaban users with NVAF, 1,914 experienced a MB event, with incidence of 2.60 (95% CI 2.49-2.72) per 100 person-years. Patient characteristics and subgroup bleeding rates are displayed in Table 1. There were 62 patients who experienced fatal bleeding, and the mean (SD) age at time of death was 79.3 (7.6) years. Among those who died, 74.2% had intracranial hemorrhage, 22.6% had gastrointestinal hemorrhage, and 3.2% had bleeding in other sites. Conclusion: The incidence, pattern, and management of MB in rivaroxaban users with NVAF in a large and diverse population were generally consistent with the findings from the registration trial. Fatal bleeding was rare.

Diabetes mellitus (DM) is a common co-morbidity in those with nonvalvular atrial fibrillation (NVAF). Most patients with DM and NVAF have a CHA 2 DS 2 -VASc score of ≥1 and should be considered for oral anticoagulation therapy for stroke prevention per treatment guidelines. The most important risk associated with anticoagulation is bleeding, which may be higher in those with NVAF plus DM. Our objective was to evaluate the incidence and characteristics of major bleeding (MB) in rivaroxaban users diagnosed with NVAF, further comparing those with DM versus those without DM, in a real-world clinical setting. Electronic medical records of >10 million patients from the Department of Defense Military Health System were queried to identify rivaroxaban users with NVAF over a 2.5-year period. Major bleeding–related hospitalization was identified by a validated case-finding algorithm. Patient characteristics, incidence and management of MB, and fatal outcomes were assessed by DM status. Of 44,793 rivaroxaban users with NVAF, 12,039 (26.9%) had DM, who were more likely men, younger, with more co-morbidity and higher CHA 2 DS 2 -VASc scores. Major bleeding incidence was higher among those with DM compared with those without, 3.68 (95% confidence interval [CI] 3.37 to 4.03) versus 2.51 (95% CI 2.34 to 2.69) per 100 person-years, and intracranial bleeding incidence was 0.19 (95% CI 0.13 to 0.28) versus 0.25 (95% CI 0.20 to 0.31) per 100 person-years. Fatal outcomes were rare for both cohorts, 0.09 per 100 person-years. In conclusion, in this post-marketing study of 44,793 rivaroxaban users with NVAF, patients with DM had more co-morbidities and higher incidence of MB compared with those without DM.

Rivaroxaban is a novel oral anticoagulant indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF). Although results from pooled analyses have shown that novel oral anticoagulants are associated with significant reductions in stroke

Background: Patients with renal impairment (as compared to those without) who receive anticoagulants appear to be at increased risk of bleeding based on recent clinical trials. Rivaroxaban is a direct factor Xa inhibitor used to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF). Purpose: To quantify the rates and better understand the pattern of major bleeding (MB) among NVAF patients with and without a coded diagnosis of renal disease (RD) who take rivaroxaban. Methods: Nearly 10 million electronic medical records from the Department of Defense healthcare system were evaluated to identify MB related hospitalizations among rivaroxaban users with NVAF over a 2 year period as part of an ongoing post-marketing study. A validated algorithm (Cunningham 2011) was used to identify MB. Renal disease (reflective of impaired renal function) was defined via diagnostic codes within 6 months prior to the bleeding date for MB cases, or the reporting quarter for non-MB patients. Rates of MB were quantified by renal disease status. Additional data were collected on patient characteristics and comorbidities, MB management, and outcomes. Results: Overall, 39,052 rivaroxaban users with NVAF were identified; 6,034 patients (15.5%) had RD. Patients with RD had a higher rate of MB than those without RD, 4.65 per 100 person-years versus 2.59 per 100 person-years, respectively. Patients with RD also had a greater prevalence of comorbidities and higher CHA 2 DS 2 -VASc scores. Key findings are presented in Table 1. Conclusion: In a post-marketing study of 39,052 rivaroxaban users with nonvalvular atrial fibrillation, patients with renal disease experienced a higher rate of MB than those without renal disease. This higher rate of MB may be partly due to the confounding effects of comorbidities in patients with RD, as reflected by their higher CHA 2 DS 2 -VASc scores, and is worthy of further investigation.

Introduction: Rivaroxaban is a novel oral anticoagulant indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). Anticoagulation therapies carry a risk of major bleeding (MB), for which patient characteristics may play a role. Methods: Using data obtained from the Department of Defense (DoD), we examined risk factors for MB within a cohort of rivaroxaban-treated patients with NVAF using a nested case-control design. Cases with MB were selected by a validated claims-based algorithm that approximates the definition of MB used in clinical trials. Incidence density sampling was used to identify 5 controls without MB for each case. Controls had the same year of entry into the cohort and were at risk for a MB event at the time of each matched case’s event (index date). Potential risk factors for MB included demographic characteristics and comorbidities from the 12 months prior to the index date. Odds ratios (OR) and 95% confidence intervals (CI) were calculated from multivariable conditional logistic regression models to identify risk factors for bleeding. Results: Among 542 MB cases and 2,710 controls, MB cases were older and had more comorbidities (Table 1). Based on the multivariable modeling, increased age, anemia, prior gastrointestinal bleeding, heart failure, and vascular disease were identified as the strongest risk factors for MB (p Conclusions: Several risk factors for MB were identified, although some findings may be affected by unmeasured confounding effects. These risk factors may assist in the development of clinical management strategies.

Study objective Assessing stroke risk associated with nonvalvular atrial fibrillation depends on the evaluation of patient characteristics and clinical features. Clinicians must determine that the net clinical benefit from anticoagulation therapy outweighs its risk, namely, bleeding. Risk assessment for stroke is commonly performed by calculating a CHA2DS2-VASc (congestive heart failure/left ventricular dysfunction, hypertension, ≥75 years, diabetes mellitus, previous stroke or transient ischemic attack or thromboembolism, vascular disease, aged 65 to 74 years, sex female) score. It is possible that CHA2DS2-VASc scores also have a relationship with the incidence of major bleeding. We examined the relationship between CHA2DS2-VASc scores and major bleeding in rivaroxaban users with nonvalvular atrial fibrillation. Methods Electronic medical records of more than 10 million patients from the Department of Defense Military Health System were queried to identify patients with nonvalvular atrial fibrillation who received rivaroxaban from January 1, 2013, to June 30, 2015. Baseline characteristics of the study population were described by CHA2DS2-VASc scores and major bleeding status; major bleeding incidence was evaluated by CHA2DS2-VASc score category and for each CHA2DS2-VASc component. Results Overall, 44,793 patients met the inclusion criteria for this analysis. The major bleeding incidence rate was 2.84 (95% confidence interval 2.69 to 3.00) per 100 person-years. The incidence of major bleeding increased from 0.30 to 5.40 per 100 person-years among patients with a CHA2DS2-VASc score of 0 to 5 or higher, respectively. Fatal outcomes among patients with major bleeding were positively correlated with CHA2DS2-VASc scores; patients with higher scores had higher mortality rates. The CHA2DS2-VASc component with the highest major bleeding incidence was for vascular disease, 5.69 (95% confidence interval 5.18 to 6.24) per 100 person-years. Conclusion Higher CHA2DS2-VASc scores are associated with increased incidence of major bleeding in nonvalvular atrial fibrillation patients receiving rivaroxaban.

Background: Cancer patients are at increased risk of both venous thromboembolism (VTE) and bleeding, but real world bleeding rates with contemporary anticoagulants are not known. Purpose: To describe the incidence of major bleeding (MB) in VTE patients treated with rivaroxaban, and to compare differences in MB incidence and characteristics among patients with active cancer, history of cancer, and no current or past cancer. Methods: We queried over 10 million electronic medical records (EMRs) from the United States Department of Defense healthcare system from November 2, 2012 to September 30, 2015 to identify MB events in VTE patients treated with rivaroxaban. The Cunningham algorithm was used for identifying MB, and VTE was determined by diagnosis codes. Presence of cancer was assessed from 5 years prior to index rivaroxaban exposure through end of study, and categorized by active cancer, history of cancer, and no cancer. Active cancer was defined by one of the following: 1) a metastatic diagnosis code within 6 months prior to or overlapping with rivaroxaban exposure, 2) chemotherapy and/or radiation codes within 6 months prior to rivaroxaban exposure, 3) cancer-related surgery overlapping with rivaroxaban exposure, or 4) leukemia and/or indolent lymphoma codes at any point within the entire assessment window. History of cancer was defined as the presence of any cancer diagnosis within the 5-year baseline period not meeting the definition of active cancer. Patients with active cancer or history of cancer were further categorized by cancer site/type. Incidence, outcomes, demographics, and bleeding risk scores were evaluated by cancer status. A Cox proportional hazard model was used to assess the association between cancer status and rate of MB adjusting for baseline characteristics. Results: The study population comprised 9,638 VTE patients on rivaroxaban, including 1,728 (17.9%) with active cancer, 1,548 (16.1%) with history of cancer and 6,362 (66.0%) with no cancer. Of these, 130 (1.3%) experienced MB. After stratifying by cancer status, MB occurred at a rate of 2.61 (95% CI 1.80-3.78) per 100 person-years in those with active cancer, 3.18 (95% CI 2.17-4.67) per 100 person-years in those with history of cancer, and 2.25 (95% CI 1.80-2.81) per 100 person-years in those with no cancer. No significant difference in the incidence of MB was found between those with cancer (active or history) and those without cancer (HR 1.01; 95% CI 0.70-1.47, p-value 0.94) after adjusting for age, sex, and baseline comorbidities. Neither history of cancer nor active cancer when independently compared to no cancer was significantly associated with MB after multivariate adjustment. MB rates varied notably by cancer site. Additional key findings are presented in Table 1. Conclusion: In this large United States Department of Defense cohort study of rivaroxaban users treated for VTE, incidence of MB is relatively low and not significantly different between cancer and non-cancer patients. Fatal outcomes associated with bleeding hospitalization were also uncommon across all the cancer groups. These data should provide assurance to oncology providers regarding the safety of rivaroxaban use in the real-world setting. Disclosures Khorana: Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Leo: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Halozyme: Consultancy, Honoraria; Janssen Scientific Affairs, LLC: Consultancy, Honoraria, Research Funding. Peacock:Phillips: Consultancy; Comprehensive Research Associates LLC: Equity Ownership; Pfizer: Research Funding; Banyan: Research Funding; Cardiorentis: Consultancy, Research Funding; Portola: Consultancy, Research Funding; Abbott: Research Funding; Emergencies in Medicine LLC: Equity Ownership; Ischemia Care: Consultancy; Janssen: Consultancy, Research Funding; Alere: Consultancy, Research Funding; Roche: Research Funding; The Medicine's Company: Consultancy, Research Funding; ZS Pharma: Consultancy, Research Funding; Prevencio: Consultancy. Yuan:Janssen Research and Development: Employment; Johnson & Johnson: Other: Mr. Yuan owns stocks in Johnson & Johnson.. Sicignano:Janssen Research and Development: Other: NMS is an employee of Health ResearchTx LLC, which has a business relationship with Janssen.. Hopf:Janssen Research and Development: Other: KPH is an independent contractor for Health ResearchTx LLC, which has a business relationship with Janssen . Patel:National Heart Lung and Blood Institute: Research Funding; Janssen: Consultancy; Bayer: Consultancy; Otsuka: Consultancy; Johnson & Johnson: Consultancy; AstraZeneca: Consultancy, Research Funding; Heart Flow Technologies: Research Funding; Agency for Healthcare Research and Quality: Research Funding.

Diabetes mellitus (DM) and atrial fibrillation (AF) are both independent risk factors for stroke. Per current clinical practice guidelines, all female and many male patients with AF who also have DM should be considered for oral anticoagulation therapy for stroke prevention. Rivaroxaban, a novel

Rivaroxaban is a novel direct factor Xa inhibitor approved for multiple indications. As part of an FDA post-marketing safety requirement, a five-year observational study was designed to evaluate major bleeding (MB) among non-valvular atrial fibrillation (NVAF) patients on rivaroxaban. Using a