Risk of interstitial lung disease in patients treated for atrial fibrillation with dronedarone versus other antiarrhythmics.

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.

Cardiovascular Outcomes and Risks After Initiation of a Sodium Glucose Cotransporter 2 Inhibitor: Results From the EASEL Population-Based Cohort Study (Evidence for Cardiovascular Outcomes With Sodium Glucose Cotransporter 2 Inhibitors in the Real World).

BACKGROUND: Clinical trials have shown cardiovascular benefits and potential risks from sodium glucose cotransporter 2 inhibitors (SGLT2i). Trials may have limited ability to address individual end points or safety concerns. METHODS: We performed a population-based cohort study among patients with type 2 diabetes mellitus with established cardiovascular disease newly initiated on antihyperglycemic agents within the US Department of Defense Military Health System between April 1, 2013, and December 31, 2016. Incidence rates, hazard ratios (HRs), and 95% confidence intervals (CIs) for time to first composite end point of all-cause mortality and hospitalization for heart failure event, major adverse cardiovascular events (defined as all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke), and individual end points were evaluated using conditional Cox models comparing new SGLT2i users with other antihyperglycemic agents. The exploratory safety end point was below-knee lower extremity amputation. Intent-to-treat and on-treatment analyses were performed. RESULTS: After propensity matching, 25 258 patients were followed for a median of 1.6 years. Compared with non-SGLT2i, initiation of SGLT2i was associated with a lower rate of all-cause mortality and hospitalization for heart failure (1.73 versus 3.01 events per 100 person-years; HR, 0.57; 95% CI, 0.50-0.65) and major adverse cardiovascular events (2.31 versus 3.45 events per 100 person-years; HR, 0.67; 95% CI, 0.60-0.75). SGLT2i initiation was also associated with an ≈2-fold higher risk of below-knee lower extremity amputation (0.17 versus 0.09 events per 100 person-years; HR, 1.99; 95% CI, 1.12-3.51). Because of the disproportionate canagliflozin exposure in the database, the majority of amputations were observed on canagliflozin. Results were consistent in the on-treatment analysis. CONCLUSIONS: In this high-risk cohort, initiation of SGLT2i was associated with lower risk of all-cause mortality, hospitalization for heart failure, and major adverse cardiovascular events and higher risk of below-knee lower extremity amputation. Findings underscore the potential benefit and risks to be aware of when initiating SGLT2i. It remains unclear whether the below-knee lower extremity amputation risk extends across the class of medication, because the study was not powered to make comparisons among individual treatments.

A plateau in new onset type 1 diabetes: Incidence of pediatric diabetes in the United States Military Health System.

OBJECTIVES: To describe the incidence and prevalence of type 1 diabetes among pediatric dependents of the US Department of Defense. METHODS: The Military Health System (MHS) data repository was used to identify pediatric patients (≤17 years of age) with type 1 diabetes from January 1, 2007 to December 31, 2012. Annual incidence, annual prevalence and adjusted incidence were calculated and stratified by sex, age group, and region of residence. RESULTS: Within a 6-year study period from 2007 to 2012, 5616 pediatric patients with type 1 diabetes were identified; 57% male, mean (SD) age of 10.9 (4.2) years. Annual type 1 diabetes incidence (per 100 000 persons) over the 5-year time period ranged from 20.7/100 000 to 21.3/100 000. Incidence for each year was highest in the 10 to 14 years age group and ranged from 30.9/100 000 in 2008 to 35.2/100 000 in 2011. Annual type 1 diabetes prevalence (per 1000 persons) remained stable throughout the study period at 1.5/1000. Adjusted incidence for males was significantly higher compared to females (21.0/100 000 vs 18.1/100 000; P = .001). During the study period, annual incidence remained steady (test for trend, P = .984). CONCLUSIONS: The incidence of type 1 diabetes among children appears to plateau during the study period, suggesting a steady state of type 1 diabetes within this pediatric population. The MHS provides an accurate and up to date look at incidence of type 1 diabetes and may reflect broader trends of incidence of pediatric disease for the United States as a whole.

Seasonal patterns of Asthma medication fills among diverse populations of the United States.

OBJECTIVE: Nonadherence to controller and overuse of reliever asthma medications are associated with exacerbations. We aimed to determine patterns of seasonal asthma medication use and to identify time period(s) during which interventions to improve medication adherence could reduce asthma morbidity. METHODS: We conducted a retrospective cohort study of asthmatics 4-50 years of age and enrolled in three diverse health insurance plans. Seasonal patterns of medications were reported by monthly prescription fill rates per 1000 individuals with asthma from 1998 to 2013, and stratified by healthcare plan, sex, and age. RESULTS: There was a distinct and consistent seasonal fill pattern for all asthma medications. The lowest fill rate was observed in the month of July. Fills increased in the autumn and remained high throughout the winter and spring. Compared with the month of May with high medication fills, July represented a relative decrease of fills ranging from 13% (rate ratio, RR: 0.87, 95% confidence interval, 95%CI: 0.72-1.04) for the combination of inhaled corticosteroids (ICS) + long acting beta agonists (LABA) to 45% (RR: 0.55, 95%CI: 0.49-0.61) for oral corticosteroids. Such a seasonal pattern was observed each year across the 16-year study period, among healthcare plans, sexes, and ages. LABA containing control medication (ICS+LABA and LABA) fill rates were more prevalent in older asthmatics, while leukotriene receptor antagonists were more prevalent in the younger population. CONCLUSIONS: A seasonal pattern of asthma medication fill rates likely represents a reactive response to a loss of disease control and increased symptoms. Adherence to and consistent use of asthma medications among individuals who use medications in reaction to seasonal exacerbations might be a key component in reducing the risk of asthma exacerbations.

CHA2DS2-VASc Scores and Major Bleeding in Patients With Nonvalvular Atrial Fibrillation Who Are Receiving Rivaroxaban.

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.

Delay in initiation of adjuvant trastuzumab therapy leads to decreased overall survival and relapse-free survival in patients with HER2-positive non-metastatic breast cancer.

Trastuzumab reduces the risk of relapse in women with HER2-positive non-metastatic breast cancer, but little information exists on the timing of trastuzumab initiation. The study investigated the impact of delaying the initiation of adjuvant trastuzumab therapy for >6 months after the breast cancer diagnosis on time to relapse, overall survival (OS), and relapse-free survival (RFS) among patients with non-metastatic breast cancer. Adult women with non-metastatic breast cancer who initiated trastuzumab adjuvant therapy without receiving any neoadjuvant therapy were selected from the US Department of Defense health claims database from 01/2003 to 12/2012. Two study cohorts were defined based on the time from breast cancer diagnosis to trastuzumab initiation: >6 months and ≤6 months. The impact of delaying trastuzumab initiation on time to relapse, OS, and RFS was estimated using Cox regression models adjusted for potential confounders. Of 2749 women in the study sample, 79.9 % initiated adjuvant trastuzumab within ≤6 months of diagnosis and 20.1 % initiated adjuvant trastuzumab >6 months after diagnosis. After adjusting for confounders, patients who initiated trastuzumab >6 months after the breast cancer diagnosis had a higher risk of relapse, death, or relapse/death than those who initiated trastuzumab within ≤6 months of diagnosis (hazard ratios [95 % CIs]: 1.51 [1.22-1.87], 1.54 [1.12-2.12], and 1.43 [1.16-1.75]; respectively). The results of this population-based study suggest that delays of >6 months in the initiation of trastuzumab among HER2-positive non-metastatic breast cancer patients are associated with a higher risk of relapse and shorter OS and RFS.

Outcomes of follow-up care after an emergency department visit among pediatric asthmatics in the military health system.

BACKGROUND AND OBJECTIVES: Asthma exacerbations frequently trigger emergency department (ED) visits. Guidelines recommend timely follow-up after an ED visit for asthma, however, other studies have questioned the quality of follow-up care and their effect on subsequent ED utilization. We evaluated follow-up care on asthma outcomes in pediatric asthmatics enrolled in the Military Health System (MHS) after an ED visit for asthma. METHODS: This retrospective study utilized MHS data to evaluate 2-17-year-old persistent asthmatics with an ED visit for asthma between 2010-2012. Demographics, medication dispensing, and subsequent asthma related ED and hospital utilization were compared between those with or without a 28-day follow-up appointment. RESULTS: 10,460 of 88,837 persistent asthmatics met inclusion criteria for an asthma ED visit. 4,964 (47.5%) had ≥ 1 follow-up visit. In the 29-365 days after their ED visit, 21.1% of the follow-up cohort required an ED re-visit compared to 24.0% of the patients without follow-up. Follow-up care was associated with a reduction in ED re-visits (adjusted hazard ratio 0.86; 95% confidence interval 0.79, 0.93). Controller medications were dispensed to 76.0% of the follow-up cohort within 90 days of their ED visit compared to 49.7% in the group without follow-up. CONCLUSIONS: Despite universal access to healthcare, less than half of pediatric MHS asthma patients had follow-up within 28 days of an ED visit. Those with follow-up were more likely to fill a controller medication within 90 days post-ED visit, and less likely to have an asthma ED re-visit in the subsequent year.

Long-Term Safety of Roflumilast in Patients with Chronic Obstructive Pulmonary Disease, a Multinational Observational Database Cohort Study.

Purpose: This study evaluated the long-term safety of roflumilast in patients with chronic obstructive pulmonary disease or chronic bronchitis using electronic healthcare databases from Germany, Norway, Sweden, and the United States (US). Patients and Methods: The study population consisted of patients aged ≥40 years who had been exposed to roflumilast and a matched cohort unexposed to roflumilast. The matching was based on sex, age, calendar year of cohort entry date (2010-2011, 2012, or 2013), and a propensity score that included variables such as demographics, markers of chronic obstructive pulmonary disease (COPD) severity and morbidity, and comorbidities. In comparison to the unexposed matched cohort (never use), three exposure definitions were used for the exposed matched cohort: ever use, use status (current, recent, past use), and cumulative duration of use. The main outcome was 5-year all-cause mortality. Cox regression models were used to estimate crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CI). Results: 112,541 unexposed and 23,239 exposed patients across countries were included. Some variables remained unbalanced after matching, indicating higher COPD disease severity among the exposed patients. Adjusted HRs of 5-year all-cause mortality for "ever use" of roflumilast, compared to "never use", were 1.12 (95% CI, 1.08-1.17) in Germany, 1.00 (95% CI, 0.92-1.08) in Norway, 0.98 (95% CI, 0.92-1.04) in Sweden, and 1.16 (95% CI, 1.12-1.20) in the US. Compared to never users, there was a decrease in 5-year mortality risk observed among "current users" in Germany (HR: 0.93, 95% CI: 0.88-0.98), Norway (HR: 0.77, 95% CI: 0.67-0.87), and Sweden (HR: 0.80, 95% CI: 0.73-0.88). Conclusion: There was no observed increase in 5-year mortality risk with the use of roflumilast in Sweden or Norway. A small increase in 5-year mortality risk was observed in Germany and the US in the ever versus never comparison, likely due to residual confounding by indication.

The Military Health System: Minimizing Disparities in Breast Cancer Treatment.

BACKGROUND: The Military Health System (MHS) is a universal health care system, in which health care disparities are theoretically minimized. This study aimed to identify disparities and assess their impact on the initiation of timely treatment for breast cancer within a universally insured population. METHODS: A retrospective cohort study was performed to evaluate the treatment of female breast cancer patients ≥18 years of age within the MHS from January 1, 2014, to December 31, 2018. Incident breast cancer was defined as ≥2 breast cancer diagnoses without a prior diagnosis of breast cancer during the three continuous years before index diagnosis. Time from index diagnosis to initial treatment was calculated and dichotomized as receiving treatment within a clinically acceptable time course. Poisson regression was used to estimate relative risk (RR) with 95% CIs. RESULTS: Among the 30,761 female breast cancer patients identified in the MHS, only 6% of patients had a prolonged time to initial treatment. Time to initial treatment decreased during the study period from a mean (SD) of 63.2 (152.0) days in 2014 to 37.1 (28.8) days in 2018 (P < 0.0001). Age, region, and military characteristics remained significantly associated with receiving timely treatment even after the adjustment of confounders. Patients 70-79 years old were twice as likely as 18-39 years olds to receive timely treatment (RR: 2.0100, 95% CI, 1.52-2.6563, P < 0.0001). Senior officers and their dependents were more likely to receive timely initial treatment compared to junior enlisted patients and their dependents (RR: 1.5956, 95% CI, 1.2119-2.1005, P = 0.004). CONCLUSIONS: There have been significant improvements in the timely initiation of breast cancer treatment within the MHS. However, demographic and socioeconomic disparities can be identified that affect the timely initiation of therapy.

Late Effects Screening of Acute Lymphoblastic Leukemia Survivors in the Military Healthcare System.

INTRODUCTION: Pediatric acute lymphoblastic leukemia (ALL) survivors are a growing portion of the population with unique health screening needs. These survivors receive care within late effects oncology clinics and primary care clinics. Prior attempts to quantify compliance with follow-up recommendations have shown variable rates ranging from 28% to 73%. This study set out to assess rates of adherence to recommended health screening among pediatric ALL survivors within the U.S. DoD, identify potential risk factors contributing to patient compliance, and better define the prevalence of chronic health conditions. MATERIALS AND METHODS: This Institutional Review Board-approved, retrospective cohort study used data from the U.S. DoD MHS database and identified incident cases of pediatric ALL during 2007-2011 using a conservative case identification algorithm. Minimum duration of follow-up was instituted in order to ensure the entire study population had sufficient time for the assessment of each screening exam according to recommended guidelines. Rates of adherence to recommended screening measures were calculated across the full study follow-up period, and regression analyses assessed protective factors for compliance. RESULTS: One hundred and forty-four incident ALL cases were identified. During the follow-up period, 31.3% developed a new mental health diagnosis. In terms of recommended screening, 94.4% had an annual complete blood count for the entire study period, 90.3% had a liver function screening, 81.9% had an echocardiogram, 34% had a bone density scan, and 54.2% had a mental health visit. Adolescents were less likely to have a bone density scan (odds ratio [OR] 0.32, 95% CI, 0.11-0.95) or a mental health visit (OR 0.28, 95% CI, 0.11-0.7). CONCLUSION: The MHS provides universal access to healthcare for all beneficiaries. In this population with universal access to care, there is increased compliance with screening recommendations. Our results reflect actual screening testing as opposed to general screening visits that have been previously reported in the literature. We also highlight the significant number of mental health diagnoses among pediatric ALL survivors.

A descriptive study of asthma in young adults conceived by IVF.

Although asthma has been previously associated with preterm delivery and low birthweight, evidence supporting a relationship between IVF and asthma remains inconclusive. The purpose of this study was to characterize asthma experiences in the oldest IVF-conceived generation in the USA. A cross-sectional study was conducted among 173 young adults (age: 18-26 years) conceived by conventional IVF between 1981 and 1990 at a major fertility treatment centre. A self-administered questionnaire was used with standard questions adapted from the 2008 Behavioural Risk Factor Surveillance System to assess asthma characteristics. Sixteen percent of participants reported a lifetime diagnosis of asthma; nearly half of those were no longer experiencing asthma symptoms at the time of the survey. The asthma profile of young adults conceived by IVF appeared to be favourable compared with the general population of the USA. Although few statistically significant results were obtained, low birthweight infants and individuals of a multiple gestation tended to be diagnosed at a later stage and were more likely to be current asthmatics seeking healthcare services than normal-weight infants and individuals of a singleton gestation. Further studies using larger samples and more advanced designs are needed to confirm these preliminary findings.

Cardiovascular outcomes and mortality after initiation of canagliflozin: Analyses from the EASEL Study.

INTRODUCTION: In the EASEL study of patients with type 2 diabetes and high cardiovascular risk, initiation of sodium glucose co-transporter 2 inhibitors (SGLT2i) was associated with lower risk of cardiovascular events and mortality and higher risk of below-knee lower extremity (BKLE) amputation versus non-SGLT2i therapies. This analysis further examined risk of cardiovascular events, cardiovascular and noncardiovascular death and BKLE amputation with the SGLT2i canagliflozin versus non-SGLT2i. METHODS: New user cohorts were constructed from Department of Defense Military Health System patients initiating canagliflozin or non-SGLT2i (4/1/2013-12/31/2016). Propensity score matching (1:1) controlled for imbalances in baseline covariates. Incidence rates, hazard ratios and 95% confidence intervals for time to first composite outcome of all-cause mortality (ACM) and hospitalization for heart failure (HHF), composite major adverse cardiovascular events (MACE) and individual components were evaluated using conditional Cox models. The National Death Index was used to differentiate cardiovascular from noncardiovascular death. The exploratory safety end-point was BKLE amputation. RESULTS: After propensity matching, 15 394 patients with well-balanced baseline covariates were followed for a median of 2.03 years (intent-to-treat). Canagliflozin showed significant benefit for ACM and HHF (P < .0001), MACE (P = .0001), cardiovascular death (P < .0001) and noncardiovascular death (P = .0018). No significant difference in risk of BKLE amputation was observed (P = .20), though few events were observed. Results were generally consistent in on-treatment analyses. CONCLUSIONS: In this high cardiovascular risk cohort studied in routine clinical practice, canagliflozin was associated with lower risk of cardiovascular events, cardiovascular death and all-cause mortality with no significant increase in BKLE amputation risk versus non-SGLT2i.

Outcomes Associated with Dronedarone Use in Patients with Atrial Fibrillation.

The antiarrhythmic drug dronedarone was designed to reduce the extra-cardiac adverse effects associated with amiodarone use in treatment of patients with atrial fibrillation / atrial flutter (AF/AFL). This epidemiological study used a retrospective cohort design to compare risk of cardiovascular-related hospitalizations and death in AF/AFL patients treated with dronedarone versus other antiarrhythmic drugs (AADs). AF/AFL patients with incident dronedarone fills were matched by propensity score (PS) to incident users of other AADs. The primary study outcome was hospitalization for cardiovascular (CV) causes within 24 months after the first study drug fill. A secondary composite outcome comprised hospitalization for CV causes or all-cause mortality during follow-up. In the AF/AFL patient cohort meeting eligibility criteria, 6,964 incident users of dronedarone and 25 607 incident users of other AADs were identified. The PS-matched cohort comprised 6,349 Dronedarone users (91.2% of all eligible) and 12,698 other AAD users. Dronedarone patients had a significantly lower risk of hospitalization for a CV event compared to Other AAD users (hazard ratio = 0.87; 95% confidence interval = 0.79 to 0.96). This was consistent with results for the composite outcome (hazard ratio=0.86; 95% confidence interval = 0.78 to 0.95). In conclusion, AF/AFL patients initiated on dronedarone versus other AADs had significantly lower risk of CV hospitalizations as well as the composite CV hospitalization / death from any cause.

Sarcoidosis in the United States Military Health System.

Rationale: Sarcoidosis is an inflammatory disorder of unclear etiology with historical significance in the U.S. Department of Defense (DoD). Objectives: This study sought to characterize the sarcoidosis population within the DoD Military Health System (MHS). Methods: Adult patients with sarcoidosis were identified in the DoD MHS database from 01-JAN-2004 through 31-DEC-2013. Patients required ≥3 encounters with a sarcoidosis diagnosis and continuous MHS eligibility. Index was defined as date of first sarcoidosis encounter. Comorbidities were assessed within the pre-index and follow-up periods. Additionally, a subset of sarcoidosis patients was identified as having conditions that can be associated with cardiac sarcoidosis. Measurements and Main Results: The final sarcoidosis cohort was 9,908 patients, 57% female, and had a mean (SD) age of 53.1 (13.6) years. The region with the largest population was the east coast (45.6%). The top 5 pre-index comorbidities were hypertension (51.7%), fatigue (27.0%), anemia (21.4%), diabetes, type II (19.6%), and coronary heart disease (16.5%). Prevalence of the following conditions increased ≥2-fold from pre-index to follow-up: leukocytopenia, pulmonary hypertension, chronic kidney disease, thrombocytopenia, hypercalcemia, venous thromboembolism, congestive heart failure, seizure disorder, stroke/TIA, hypercalciuria, and arthritis. Of the sarcoidosis cohort, 21.8% (n=2,164) were identified as having cardiac conditions that can be associated with cardiac sarcoidosis. The top conditions in this cohort were cardiac arrhythmia (75.6%), congestive heart failure (20.4%), and cardiomyopathy (13.6%). Conclusions: The MHS has a large population of sarcoidosis patients, of which 22% had cardiac conditions that can be associated with granulomatous inflammation of the heart. Prevalence of numerous comorbid conditions increased after sarcoidosis diagnosis. (Sarcoidosis Vasc Diffuse Lung Dis 2018; 35: 261-267).

Incidence and characteristics of major bleeding among rivaroxaban users with renal disease and nonvalvular atrial fibrillation.

OBJECTIVE: Patients with nonvalvular atrial fibrillation (AF) and renal disease (RD) who receive anticoagulation therapy appear to be at greater risk of major bleeding (MB) than AF patients without RD. As observed in past studies, anticoagulants are frequently withheld from AF patients with RD due to concerns regarding bleeding. The objective of this study was to evaluate the incidence and pattern of MB in those with RD, as compared to those without RD, in a population of rivaroxaban users with nonvalvular AF. METHODS: Electronic medical records of over 10 million patients from the Department of Defense Military Health System were queried to identify rivaroxaban users with nonvalvular AF. A validated algorithm was used to identify MB-related hospitalizations. RD was defined through diagnostic codes present within 6 months prior to the bleeding date for MB cases and end of study participation for non-MB patients. Data were collected on patient characteristics, comorbidities, MB management, and outcomes. RESULTS: Overall, 44,793 rivaroxaban users with nonvalvular AF were identified. RD was present among 6,921 patients (15.5%). Patients with RD had a higher rate of MB than those without RD, 4.52 per 100 person-years versus 2.54 per 100 person-years, respectively. The fatal bleeding outcome rate (0.09 per 100 person-years) was identical between those with and without RD. CONCLUSION: In this post-marketing study of 44,793 rivaroxaban users with nonvalvular AF, RD patients experienced a higher MB rate than those without RD. The higher rate of MB among those with RD may be due to the confounding effects of comorbidities.

Repeat Hospitalizations Predict Mortality in Patients With Heart Failure.

INTRODUCTION: Heart failure (HF) affects more than 5.1 million Americans and is projected to increase. Understanding the relationship between hospitalization and mortality can help to guide clinical management. The aim of the study is to evaluate the impact of repeat HF hospitalizations on all-cause mortality and to determine risk variables related to patient mortality. MATERIALS AND METHODS: Using administrative data from the Military Health System, a cohort of patients with an index admission for HF between 2007 and 2011 was identified. HF hospitalizations were defined as any hospital claim with an International Classification of Diseases, Ninth Revision diagnosis of 428.xx in the primary diagnosis field over the 7-year study period (2007-2013). Patients were subsequently categorized based on total number of HF hospitalizations. A multivariate Cox regression model, adjusting for age, sex, and comorbidities, was used to estimate hazard ratios. Kaplan-Meier survival curves were constructed based on the frequency of HF hospitalizations. RESULTS: Of the 51,286 patients admitted for HF, 54.7% were male with a mean (SD) age of 76.3 (10.8) years, and 29,714 died during 135,211 person-years of follow-up. Mean survival time was 2.6, 1.8, 1.5, and 1.3 years after the first, second, third, and fourth hospitalization, respectively. The mortality rate of patients at 30 days and 1 year postindex HF hospitalization was 7.4% and 27.3%, respectively. A history of dementia and chronic kidney disease without dialysis decreased overall survival. CONCLUSIONS: Repeat HF hospitalizations remain a strong predictor of mortality for existing patients with HF. As a result, clinicians and patients can individualize the optimal treatment strategy and resources on the basis of the suspected prognosis.

Comparison of the Incidence of Major Bleeding With Rivaroxaban Use Among Nonvalvular Atrial Fibrillation Patients With Versus Without Diabetes Mellitus.

Diabetes mellitus (DM) is a common co-morbidity in those with nonvalvular atrial fibrillation (NVAF). Most patients with DM and NVAF have a CHA2DS2-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 CHA2DS2-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.

The impact of temperature and relative humidity on spatiotemporal patterns of infant bronchiolitis epidemics in the contiguous United States.

Infant bronchiolitis is primarily due to infection by respiratory syncytial virus (RSV), which is highly seasonal. The goal of the study is to understand how circulation of RSV is impacted by fluctuations in temperature and humidity in order to inform prevention efforts. Using data from the Military Health System (MHS) Data Repository (MDR), we calculated rates of infant bronchiolitis for the contiguous US from July 2004 to June 2013. Monthly temperature and relative humidity were extracted from the National Climate Data Center. Using a spatiotemporal generalized linear model for binomial data, we estimated bronchiolitis rates and the effects of temperature and relative humidity while allowing them to vary over location and time. Our results indicate a seasonal pattern that begins in the Southeast during November or December, then spreading in a Northwest direction. The relationships of temperature and humidity were spatially heterogeneous, and we find that climate can partially account for early onset or longer epidemic duration. Small changes in climate may be associated with larger fluctuations in epidemic duration.

A post-marketing assessment of major bleeding in total hip and total knee replacement surgery patients receiving rivaroxaban.

BACKGROUND: 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. OBJECTIVE: To evaluate major bleeding (MB) in THR/TKR patients receiving post-operative rivaroxaban. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Characteristics and Medication Use of Psoriasis Patients Who May or May Not Qualify for Randomized Controlled Trials.

BACKGROUND: Clinical trials impose exclusion criteria that may limit the generalizability of results. OBJECTIVES: To (a) determine the percentage of real-world patients who would qualify for psoriasis randomized controlled trials; (b) ascertain differences between moderate-to-severe psoriasis patients who would be eligible, ineligible, or potentially eligible for clinical trials; and (c) compare their biologic treatment patterns. METHODS: Moderate-to-severe psoriasis patients were identified from the U.S. Department of Defense health care database from January 1, 2008, to October 31, 2013. Eligibility classification for psoriasis trials was based on common trial exclusion criteria involving medical conditions and recent treatment history. Patient characteristics and treatment patterns of 4 biologics (adalimumab, etanercept, infliximab, and ustekinumab) were compared between groups. Adherence was measured by medication possession ratio and persistence as continuous time on drug with ≤ 90-day gap between supply times. RESULTS: Among 16,284 qualifying psoriasis patients, 4,677 (28.7%) were medically ineligible, and 8,466 (52.0%) had ineligibility-related treatments that could be stopped prior to trial entry; the latter patients were considered potentially eligible for psoriasis trials. Common reasons for medical ineligibility included malignancies and hematologic disorders; treatment ineligibilities included use of topical corticosteroids and phototherapy. Medically ineligible patients were older and had more comorbidities, while potentially eligible patients were younger and healthier than trial-eligible patients. Most treatment patterns were similar across groups, except that, compared with the trial-eligible group, medically ineligible patients had greater adherence to infliximab and potentially trial-eligible patients had greater adherence and persistence to adalimumab. CONCLUSIONS: This large real-world study found that patients who may be ineligible for psoriasis trials differ in important respects (e.g., comorbidities, prior treatments) from their trial-eligible counterparts. Regardless of their differences at baseline, adherence, persistence, and switching of biologic medications are largely similar, with few differences noted among groups. DISCLOSURES: Financial support for this study was provided by Lilly USA. Wu has received research funding from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Coherus Biosciences, Dermira, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Regeneron, Sandoz, and Sun Pharmaceutical Industries, and he is a consultant for AbbVie, Amgen, Celgene, Dermira, Eli Lilly, Pfizer, Regeneron, and Sun Pharmaceutical Industries. Malatestinic, Goldblum, Solotkin, Lin, Johnston, and Araujo are employees and/or stock owners of Lilly. Nordstrom, Kistler, and Fraeman are employees of Evidera, which received funding from Lilly to conduct this study. LCDR Hawley is a military service member. This work was prepared as part of her official duties. Title 17 U.S.C. 105 provides that "copyright protection under this title is not available for any work of the United States Government." Title 17 U.S.C. 101 defines a U.S. government work as a work prepared by a military service member or employee of the U.S. government as part of that person's official duties. Research data were derived from an approved Naval Medical Center, Portsmouth, Virginia, institutional review board protocol. The views expressed in this work are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. government. Study concept and design were contributed by Malatestinic and Araujo, along with the other authors. Nordstrom, Kistler, Fraeman, and Sicignano collected the data, and data interpretation was performed by Wu, Lin, and Hawley, along with Malatestinic, Nordstrom, Solotkin, and Araujo. The manuscript was written by Johnston, Malatestinic, Kistler, Wu, and Araujo, along with Nordstrom, Goldblum, Solotkin, Hawley, and Sicignano, and revised by Goldblum, Solotkin, Malatestinic, and Araujo, along with Nordstrom, Wu, Fraeman, Johnston, Hawley, and Sicignano.