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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). 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). 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). 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.

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. 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. 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. 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.

Understanding the long-term safety of disease-modifying therapies for multiple sclerosis (MS) in routine clinical practice can be undertaken through registry-based studies. However, variability of data quality across such sources poses the challenge of data fit for regulatory decision-making. CLARION, a non-interventional cohort safety study of cladribine tablets, combines aggregated data from MS registries/data sources, except in Germany (which utilizes primary data collection). We describe the application of key data quality indicators (DQIs) within CLARION to evaluate data quality over time, as recommended by the European Medicines Agency (EMA) guideline on registry-based studies. DQIs were defined with participating registries/sources; they were used to assess data quality according to the EMA Data Quality Framework, addressing consistency, accuracy, completeness, and study representativeness. DQIs were associated with potential remedial measures if data quality was not met. DQIs were summarized overall and for individual MS registries/data sources to November 1, 2022. A total of 28 DQIs were analyzed using data from 5069 patients arising from eight MS registries/data sources and 14 countries. The Representativeness DQIs showed that 72.0% of patients were female, median age at MS diagnosis was 29.0 to 43.3 years, and 93.5% had relapsing-remitting MS. Consistency DQIs showed a total of 2899 patients had achieved at least two years of follow-up; 6.9% did not have any recorded visits during this timeframe. Discrepant values were assessed as part of Accuracy DQIs, and improvements over time were noted for recorded dates of MS onset and diagnosis. Regarding Completeness DQIs, 191/5069 (3.8%) patients were lost to follow-up. The application of 28 DQIs within the CLARION study has helped with understanding, not only intrinsic and question-specific determinants of data quality, but also tracking the quality of post-authorization safety data obtained from MS registries/data sources, thereby providing a foundation for the regulatory decision-making process.

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. This retrospective new user cohort study examined the risk of cardiovascular events, cardiovascular and noncardiovascular death and below‐knee lower extremity amputation with the sodium glucose co‐transporter 2 inhibitor canagliflozin versus non‐sodium glucose co‐transporter 2 inhibitors in 15 394 propensity‐score matched high cardiovascular risk patients in routine clinical practice. Canagliflozin showed significant benefit for all‐cause mortality and hospitalization for heart failure (P < .0001), major adverse cardiovascular events (P = .0001), cardiovascular death (P < .0001) and noncardiovascular death (P = .0018) compared with non‐sodium glucose co‐transporter 2 inhibitors. No significant difference in risk of below‐knee lower extremity amputation was observed (P = .20), though few events were observed.

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.

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.

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.

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 allcause 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 Conclusion: There was no observed increase in 5-year mortality risk with the use of roflumilast in Sweden or Norway. A small confounding by indication.

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.