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Epidemiology and pharmacoepidemiology frequently employ Real-World Data (RWD) from healthcare teams to inform research. These data sources usually include signs, symptoms, tests, and treatments, but may lack important information such as the patient's diet or adherence or quality of life. By harnessing digital tools a new fount of evidence, Patient (or Citizen/Person) Generated Health Data (PGHD), is becoming more readily available. This review focusses on the advantages and considerations in using PGHD for pharmacoepidemiological research. New and corroborative types of data can be collected directly from patients using digital devices, both passively and actively. Practical issues such as patient engagement, data linking, validation, and analysis are among important considerations in the use of PGHD. In our ever increasingly patient-centric world, PGHD incorporated into more traditional Real-Word data sources offers innovative opportunities to expand our understanding of the complex factors involved in health and the safety and effectiveness of disease treatments. Pharmacoepidemiologists have a unique role in realizing the potential of PGHD by ensuring that robust methodology, governance, and analytical techniques underpin its use to generate meaningful research results.

The study objective was to evaluate the safety and effectiveness of dabigatran and other direct oral anticoagulants (DOACs) compared with warfarin among patients with nonvalvular atrial fibrillation using a prospective monitoring program. We implemented a cohort design with propensity score matching to compare initiators of DOACs and warfarin between 2010 and 2015 in two US healthcare databases. Proportional hazards regression was used to estimate hazard ratios (HRs) for stroke and major bleeding. The final analyses included 29,448 dabigatran, 35,520 rivaroxaban, and 19,588 apixaban initiators, matched to warfarin initiators. The pooled HR for stroke was 0.75 (95% confidence interval (CI) 0.58-0.98) for dabigatran, 0.77 (95% CI 0.61-0.98) for rivaroxaban, and 0.69 (95% CI 0.50-0.96) for apixaban, consistent with findings from randomized trials. For major hemorrhage, the HRs were 0.72 (95% CI 0.65-0.80), 1.02 (95% CI 0.94-1.12), and 0.56 (95% CI 0.49-0.64), respectively, showing a decreased risk of major bleeding for both dabigatran and apixaban, as compared with trial evidence.

Background: Idiopathic pulmonary fibrosis (IPF) is a life-threatening interstitial lung disease (ILD). Characterizing health outcomes of IPF patients is challenging due to disease rarity. Objective: This study aimed to identify the burden of disease in patients newly diagnosed with IPF. Methods: Patients with ≥1 claim with an IPF diagnosis were identified from a United States healthcare insurer’s database (2000–2013). Patients with other known causes of ILD or aged Results: Median age of newly diagnosed patients (n = 7,298) was 62 years (54.0% male). Restricting to patients with IPF diagnostic testing did not substantially affect cohort characteristics, nor did ICD-9 IPF coding change. Mean follow-up was 1.7 years; 16.8% of patients died; and a substantial proportion of patients were censored due to end of health plan enrollment (50.7%) and other causes of ILD (19.6%). The incidence of pulmonary hypertension, lung cancer, and claims-based algorithm proxy for acute respiratory worsening of unknown cause was 22.5, 17.6, and 12.6 per 1,000 person-years, respectively. Conclusions: Patients with IPF had a high disease burden with a variety of health outcomes observed, including a high rate of mortality. Database censoring due to changes in enrollment or other ILD diagnoses limited follow-up. Altering cohort entry definitions, including IPF testing or ICD-9 IPF coding change, had little impact on cohort baseline characteristics.

GLORIA-AF is a large, ongoing, prospective, global registry program run in 3 phases, assessing long-term safety and effectiveness of dabigatran etexilate (dabigatran) in patients with newly diagnosed atrial fibrillation (AF) in clinical practice. This report provides the final analysis of 2-year clinical outcomes of the full cohort of 4873 patients prescribed dabigatran and followed for a mean of 18.0 +/- 9.4 months out of the 15,308 eligible patients enrolled in Phase II (2011-2014). The overall incidence rates per 100 person-years were: stroke 0.65 (95% CI 0.48-0.87), major bleeding 0.97 (0.76-1.23) and myocardial infarction (MI) 0.50 (0.35-0.69), with observed event rates broadly consistent in all study regions, which confirms the sustained safety and effectiveness of dabigatran over 2 years of observation in clinical practice.

Aims/Introduction To evaluate linagliptin prescribing in type 2 diabetes mellitus patients with different comorbidities, an expanded Japanese post‐marketing surveillance also collected baseline data for patients initiating other glucose‐lowering drugs. Materials and Methods Patients initiating linagliptin monotherapy were enrolled, then the next patient starting monotherapy with another glucose‐lowering drug was enrolled (2012–2014). Baseline data were collected and analyzed by the Medical Dictionary for Regulatory Activities system organ class. Analyses were descriptive, and meaningful differences defined as absolute standardized difference >10%. Results Over 4,200 type 2 diabetes mellitus patients were enrolled. Most system‐organ class comorbidities were more common in patients initiating linagliptin versus other glucose‐lowering drugs, with meaningful differences observed for metabolism/nutritional (50.5 vs 45.5%, respectively), cardiac (12.2 vs 8.6%, respectively), vascular (56.4 vs 51.3%, respectively) and renal/urinary disorders (9.9 vs 5.7%, respectively). Conclusions Expanding the linagliptin Japanese post‐marketing surveillance revealed linagliptin prescribing to a type 2 diabetes mellitus population with more comorbidities versus other glucose‐lowering drugs. Although such preferential prescribing might be expected, as linagliptin requires no dose adjustment or monitoring in renally or hepatically impaired patients, this innovative post‐marketing surveillance approach generated important evidence that could only be shown in such a non‐randomized comparative study. These data generated insights important for the design and interpretation of observational studies and spontaneous reports, which are key for public health.

Jeremy A Rassen,1 Dorothee B Bartels,2 Sebastian Schneeweiss,1,3,4 Amanda R Patrick,1 William Murk1,5 1Aetion, Inc, New York, NY, USA; 2BI X GmbH, Ingelheim, Germany; 3Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Boston, MA, USA; 4Harvard Medical School, Boston, MA, USA; 5Jacobs School of Medicine, University at Buffalo, Buffalo, NY, USA Background: Health care databases are natural sources for estimating prevalence and incidence of chronic conditions, but substantial variation in estimates limits their interpretability and utility. We evaluated the effects of design choices when estimating prevalence and incidence in claims and electronic health record databases. Methods: Prevalence and incidence for five chronic diseases at increasing levels of expected frequencies, from cystic fibrosis to COPD, were estimated in the Clinical Practice Research Datalink (CPRD) and MarketScan databases from 2011 to 2014. Estimates were compared using different definitions of lookback time and contributed person-time. Results: Variation in lookback time substantially affected estimates. In 2014, for CPRD, use of an all-time vs a 1-year lookback window resulted in 4.3–8.3 times higher prevalence (depending on disease), reducing incidence by 1.9–3.3 times. All-time lookback resulted in strong temporal trends. COPD prevalence between 2011 and 2014 in MarketScan increased by 25% with an all-time lookback but stayed relatively constant with a 1-year lookback. Varying observability did not substantially affect estimates. Conclusion: This framework draws attention to the underrecognized potential for widely varying incidence and prevalence estimates, with implications for care planning and drug development. Though prevalence and incidence are seemingly straightforward concepts, careful consideration of methodology is required to obtain meaningful estimates from health care databases. Keywords: epidemiology, epidemiologic methods, epidemiological monitoring, sentinel surveillance, pharmacoepidemiology, cross-sectional studies, secondary databases, prevalence, prevalence studies, incidence

Background: We aimed to assess the extent to which drug persistence is better with non-vitamin K antagonist oral anticoagulants (NOACs) than vitamin K antagonists (VKAs) in atrial fibrillation (AF) patients and to estimate the difference in therapy persistence depending on NOAC dosing regimen (once daily (QD) vs. twice daily (BID)). Methods: Consecutive patients were followed for 1 year in phase III of the GLORIA-AF registry. Drug persistence was defined as the use of OAC without any discontinuation in &gt, 30 days or switching to alternative therapy. Results: Among 21,109 eligible patients in phase III, 17,266 patients who were prescribed OAC at baseline and those who took &ge, 1 OAC dose were included. The 1-year proportion of patients receiving NOAC and VKA who persisted on treatment was 80% and 75%, respectively. The 1-year persistence with NOACs BID and NOACs QD was 81% and 80%, respectively. Female gender, hypertension, older age, alcohol use, permanent, asymptomatic, and minimally symptomatic AF were associated with better OAC persistence. Region, medication usage predisposing to bleeding, being a current smoker, treatment reimbursement, and proton pump inhibitors were associated with lower OAC persistence. Conclusions: Drug persistence was higher with NOACs (1-year persistence was 80%) than with VKAs (75%). There was little difference in 1-year persistence between NOAC dosing regimens.

Many real-world data analyses use common data models (CDMs) to standardize terminologies for medication use, medical events and procedures, data structures, and interpretations of data to facilitate analyses across data sources. For decision makers, key aspects that influence the choice of a CDM may include (i) adaptability to a specific question; (ii) transparency to reproduce findings, assess validity, and instill confidence in findings; and (iii) ease and speed of use. Organizing CDMs preserve the original information from a data source and have maximum adaptability. Full mapping data models, or preconfigured rules systems, are easy to use, since all raw codes are mapped to medical constructs. Adaptive rule systems grow libraries of reusable measures that can easily adjust to preserve adaptability, expedite analyses, and ensure study-specific transparency.

Purpose Our goal was to describe the management of pregestational diabetes in pregnant women in the United Kingdom. Methods We used electronic medical records from The Health Improvement Network database between January 1995 and June 2012 to identify the first pregnancy in women 15 to 45 years of age with pregestational diabetes type 1 or type 2. Information on lifestyle factors, demographic characteristics, prescription of specific antidiabetic medications, and glycemic control measures (HbA1c) was obtained from primary care provider records. We evaluated treatment patterns and HbA1c levels within 90 days before the last menstrual period (prepregnancy period) and within each trimester of pregnancy. Results In a cohort of 1511 pregnant women with pregestational diabetes, 60% had type 1 and 40% type 2 diabetes. Among women with type 1 diabetes, 90% received antidiabetic medication (primarily insulin) prepregnancy and 92% during the first trimester. Among women with type 2 diabetes, 54% received antidiabetic medication (primarily metformin) during the prepregnancy period and 60% during the first trimester. Among women with nontreated diabetes type 2 before pregnancy, 22% initiated treatment by the first trimester (primarily insulin); those on noninsulin antidiabetic medications often switched to insulin. The proportion of women with at least 1 HbA1c value recorded within the prepregnancy period was 33% for type 1 (n = 299) and 31% for type 2 diabetes (n = 189); the corresponding proportions within the first trimester were 48% and 40%, respectively. Among women with recorded HbA1c, the prevalence of HbA1c > 7% prepregnancy was 70% for type 1 and 52% for type 2 diabetes; the proportions within the first trimester were 73% and 46%, respectively. Conclusions Management of pregnant women with diabetes seems to follow recommendations for pharmacological treatment. However, there is substantial room for improvement in HbA1c control, that is, in the planning of pregnancy in women with diabetes, in the initiation of antidiabetic medication among women with diabetes type 2 who may need it, and likely in the compliance with treatments in women with type 2 and type 1 diabetes.

Aims To evaluate the association between use of non-insulin antidiabetics in early pregnancy and the risk of miscarriages, stillbirths and major structural malformations. Materials and methods A cohort of 1511 pregnant women with pre-gestational diabetes linked to live births was identified using electronic medical records from The Health Improvement Network (THIN) for the period 1995 to 2012. Information on prescriptions, foetal outcomes and potential confounders was ascertained from both codes and free text in the THIN database. Odds ratios (OR) and 95% confidence intervals (CI) of adverse foetal outcomes in women treated with non-insulin antidiabetics during the first trimester compared to those on insulin were estimated using logistic regression to adjust for type of diabetes, glycaemic control and other maternal characteristics. Results Among 311 pregnant women on non-insulin antidiabetics, 21.9% had a miscarriage and 1.6% a stillbirth; 1.9% of live births had major malformations. The corresponding frequencies for the 883 women on insulin were 13.3%, 1.7% and 9.6%. Insulin users more often had type 1 diabetes and poor glycaemic control. Compared to women with type 1 diabetes, those with type 2 diabetes had a higher risk of miscarriages (20.5% vs 12.8%) but a lower prevalence of malformations (4.0% vs 9.2%). Compared to women with HbA1c ≤7%, those with HbA1c >7% had a higher prevalence of malformations (12.6% vs 2.7%). After adjustment for diabetes type and glycaemic control, compared to insulin, non-insulin antidiabetic patients were associated with an OR for miscarriage of 1.19 (95% CI, 0.75-1.89), for stillbirths of 0.65 (95% CI, 0.16-2.58), and for major malformations of 0.25 (95% CI, 0.08-0.84). Conclusion Among women with diabetes, use of non-insulin antidiabetics early in pregnancy was not associated with greater risks of foetal losses or major malformations than was insulin.

AIM To evaluate the extent to which balance in unmeasured characteristics of patients with type 2 diabetes (T2DM) was achieved in claims data, by comparing against more detailed information from linked electronic health records (EHR) data. METHODS Within a large US commercial insurance database and using a cohort design, we identified patients with T2DM initiating linagliptin or a comparator agent within class (ie, another dipeptidyl peptidase-4 inhibitor) or outside class (ie, pioglitazone or a sulphonylurea) between May 2011 and December 2012. We focused on comparators used at a similar stage of diabetes to linagliptin. For each comparison, 1:1 propensity score (PS) matching was used to balance >100 baseline claims-based characteristics, including proxies of diabetes severity and duration. Additional clinical data from EHR were available for a subset of patients. We assessed representativeness of the claims-EHR-linked subset, evaluated the balance of claims- and EHR-based covariates before and after PS-matching via standardized differences (SDs), and quantified the potential bias associated with observed imbalances. RESULTS From a claims-based study population of 166 613 patients with T2DM, 7219 (4.3%) patients were linked to their EHR data. Claims-based characteristics in the EHR-linked and EHR-unlinked patients were similar (SD

Objective Epidemiological data on genitourinary infections (GUIs) comparing patients with and without type 2 diabetes (T2DM) is scant. We aimed to estimate the incidence of urinary tract infections (UTIs), genital infections (GIs), or any GUI in total and stratified by history of GUI and sex. Research design and methods We identified 39,295 patients in the Kaiser Permanente Northwest health plan with T2DM and an equal number of age and sex matched patients without diabetes. The cohort was followed for up to 9years (2006–2014). We calculated incidence rates and corresponding 95% confidence intervals (CI) of any GUI, UTIs and GIs adjusting for age, sex, race, BMI, presence of chronic kidney disease, annual number of outpatient visits, and diuretic use. Results Adjusted incidence of any GUI was 97.2/1000person-years (p-y) (95% CI 95.5–98.8) among the T2DM cohort vs. 79.7/1000 p-y (78.3–81.2) among those without diabetes. T2DM was associated with an adjusted 25% increased risk of UTI (rate ratio 1.25, 95% CI 1.22–1.29), a 26% increased risk of GI (1.26, 1.22–1.31) and a 22% increased risk of any GUI (1.22, 1.19–1.25). Incidence rates were lower among those with no GUI history, but the relative risks were similar. Women in both groups had higher incidence rates of GUIs than men. Conclusions T2DM was associated with increased risks of any GUI, UTIs and GIs. Incidence rates of UTIs were higher than rates of GIs, but the relative risk of GIs was essentially identical. A similar pattern was observed when stratifying by sex. Significance of the study •Limited research suggests the risk of genitourinary infections is greater among patients with diabetes compared with nondiabetic individuals. •Our findings confirm the elevated risk of genitourinary infections and further show that the risk is greater among women and persist when limiting the analysis to patients with no prior history of genitourinary infections. •Clinicians should be alert to the increased risk of genitourinary infections especially among patients with newly diagnosed diabetes and long-term exposure to hyperglycemia. Research questions •Exposure to hyperglycemia may be a more important risk factor for new cases of genitourinary infections vs. historically recurrent cases among patients with diabetes, a possibility that warrants further investigation. •More research is needed to determine whether hyperglycemia increases the risk of new genitourinary infections in a dose/time-dependent manner. •The extent to which genitourinary infections increase the risk of chronic kidney disease needs more study.

Background: GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic t...

Real world data on the cardiovascular (CV) safety and effectiveness of linagliptin (LINA) complement trial data from CARMELINA, which showed CV safety, and CAROLINA (results pending). As part of a 5-year (05/2011-12/2016) post-marketing monitoring program, using 2 large insurance claims databases, we assessed the risk of a composite CV (cCV) outcome (hospitalization for myocardial infarction, stroke, unstable angina, or coronary revascularization). We identified three 1:1 propensity score (PS)-matched cohorts of type 2 diabetes mellitus patients who initiated linagliptin or a comparator [other DPP-4is (n=39,834 pairs), pioglitazone (PIO; n=29,646 pairs), or sulfonylureas (SU; n=25,285 pairs). We estimated pooled HR and 95% CI controlling for over 180 baseline characteristics. After PS-matching, patient characteristics were similar (Table 1) and mean follow-up was 0.8 years. LINA had a similar risk of the cCV outcome compared to other DPP-4is [HR (95% CI) = 0.90 (0.80-1.02)] and PIO [HR (95% CI) = 0.99 (0.86-1.13)], but was associated with a reduced risk compared to SU [HR (95% CI) = 0.77 (0.66-0.90)] (Table 1). Results were robust across numerous sensitivity analyses. These real-world data show that LINA has reassuring effectiveness and safety on a cCV outcome compared to other DPP-4is and PIO, and is associated with a decreased risk compared to SU. Disclosure E. Patorno: Research Support; Self; National Institute on Aging. Other Relationship; Self; Boehringer Ingelheim International GmbH. C. Gopalakrishnan: None. M. Mahesri: None. K.G. Brodovicz: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. D. Bartels: Employee; Self; BI X GmbH, Boehringer Ingelheim International GmbH. A. Meyers: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. J. Barberio: None. J. Liu: None. S. Schneeweiss: Consultant; Self; Aetion, WHISCON, LLC. Funding Boehringer Ingelheim

BACKGROUND: There are limited real-world data on the comparative cardiovascular (CV) safety of linagliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4i) available since May 2011. OBJECTIVES: We aimed to evaluate the safety of linagliptin vs. other glucose-lowering medications in a multi-year monitoring program using insurance claims data. METHODS: In two commercial U.S. claims databases, we identified three pairwise 1:1 propensity score (PS) matched cohorts of type 2 diabetes (T2D) patients ≥18 years initiating linagliptin or a comparator [other DPP-4i (n=31,492 pairs), pioglitazone (n=23,316 pairs), or 2(nd) generation sulfonylureas (n=19,731 pairs)] between May 2011 and December 2015. The primary endpoint was the risk of a composite CV outcome (hospitalization for myocardial infarction, stroke, unstable angina, or coronary revascularization). We estimated pooled hazard ratios (HR) and 95% confidence intervals (CI) controlling for >100 baseline characteristics. RESULTS: Patient characteristics were well balanced after PS-matching. Mean age was 55 years and mean follow-up was 0.8 years. Linagliptin had a similar risk of the composite CV outcome compared to other DPP-4is (HR = 0.91; 95% CI = 0.79–1.05) and pioglitazone (0.98; 0.84–1.15), and showed a reduced risk of CV outcomes compared to 2(nd) generation sulfonylureas (0.76; 0.64–0.92). Key findings signaled at the first interim analysis in June 2013 and solidified during ongoing monitoring through 2015. CONCLUSION: Analyses from a large monitoring program in routine care of patients with T2D, showed that linagliptin had similar cardiovascular safety compared to other DPP-4i and pioglitazone, and a reduced cardiovascular risk compared to sulfonylureas.

Aims To assess antithrombotic therapy choices in relation to patient age in a large, global registry on atrial fibrillation (AF). Methods and results Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) is an international programme involving patients with newly diagnosed AF and ≥1 risk factors for stroke. We used Phase II data (from November 2011 through December 2014), which commenced immediately following first non-vitamin K antagonist oral anticoagulants (NOACs) approval in participating countries. Of 15 092 patients (mean age 70.5 ± 11.0 years), enrolled at 982 centres, 26.9% were aged Conclusion Despite geographic differences in OAC use, neither OAC nor NOAC uptake was lower for patients ≥85 years old compared with younger patients. Although the majority of patients was prescribed OAC at all ages, nearly one-third received antiplatelet monotherapy when bleeding risk was increased. Clinical trial registration http://www.clinicaltrials.gov. Unique identifier: NCT01468701

Background: The increasing availability of electronic healthcare data enables ongoing monitoring of the effectiveness and safety of newly marketed medications. We sought to demonstrate a 5-year prospective monitoring system of dabigatran for stroke prevention that may expedite discovery and allow ongoing evidence development. Methods and Results: Between 2011 and 2015, we conducted 9 sequential analyses of dabigatran versus warfarin users in a sequential cohort design in 2 US claims databases. Analyses 4 through 9 were prespecified, and analyses 1 through 3 were added subsequently using the same methodology. New users of anticoagulants with nonvalvular atrial fibrillation were followed until a study outcome of hospitalization for stroke (hemorrhagic and ischemic) or hospitalization for major hemorrhage (intracranial and extracranial). Hazard ratios and 95% CIs were estimated after 1:1 propensity score matching. Sequential analyses 1 through 3 on stroke prevention using data through June 2012 were limited by few events leading to wide CIs. As data accumulated the effect estimate in analysis 4 visually stabilized at a 25% risk reduction with increasingly narrower CIs (−46% to +9% in December 2012 and −42% to −2% in September 2015). Improved data-adaptive confounding adjustment with high-dimensional propensity score reached a stable state already at analysis 3 and was slightly closer to the randomized clinical trial finding (−39%). The risk of major hemorrhage was 28% lower in dabigatran initiators (−35% to −20%) a finding that was stable throughout analyses 2 to 9. Conclusions: Prospectively monitoring the effectiveness and safety of dabigatran for stroke prevention allowed for early insights with increasing precision over time.

Claims databases provide information on the effects of direct oral anticoagulants (DOACs) as used in routine care but may not contain important data on clinical characteristics, which may be captured in electronic health records (EHRs). Within a US claims database, we identified patients initiating a DOAC or warfarin between October 2010 and December 2014. Propensity score (PS) matching, 1:1, was used to balance 78 claims-defined baseline characteristics. We evaluated whether balance was achieved in patient characteristics immeasurable in the claims data study by evaluating the balance in clinical information (using absolute standardized differences (aSDs)) from linked EHR data. From a claims data cohort study of 140,187 patients, 5,935 (4.2%) were linked to EHR data. After PS matching, almost all EHR-defined patient characteristics were well balanced (aSD < 0.1). A new user active comparator design with 1:1 PS matching on many patient characteristics improved balance on clinical risk factors observed in EHRs but not in claims data.

In alignment with the International Council of Harmonization’s strategic goals, a public-private consortium has developed a structured template for planning and reporting on the implementation of real world evidence (RWE) studies of the safety and effectiveness of treatments. The template serves as a guiding tool for designing and conducting reproducible RWE studies; set clear expectations for transparent communication of RWE methods; reduce misinterpretation of prose that lacks specificity; allow reviewers to quickly orient and find key information; and facilitate reproducibility, validity assessment, and evidence synthesis. The template is intended for use with studies of the effectiveness and safety of medical products and is compatible with multiple study designs, data sources, reporting guidelines, checklists, and bias assessment tools.

The scientific community and decision-makers are increasingly concerned about transparency and reproducibility of epidemiologic studies using longitudinal healthcare databases. We explored the extent to which published pharmacoepidemiologic studies using commercially available databases could be reproduced by other investigators. We identified a nonsystematic sample of 38 descriptive or comparative safety/effectiveness cohort studies. Seven studies were excluded from reproduction, five because of violation of fundamental design principles, and two because of grossly inadequate reporting. In the remaining studies, >1,000 patient characteristics and measures of association were reproduced with a high degree of accuracy (median differences between original and reproduction

Essentials Unlike warfarin, treatment with DOACs do not require regular plasma level monitoring. We compared persistence of patients treated with DOACs compared to warfarin. Persistence at 12 months was higher for all DOACs compared to warfarin. Persistence to anticoagulant therapy was generally poor in commercially insured patients. Background Direct oral anticoagulants (DOACs) were developed as an alternative to vitamin K antagonists for a variety of indications. Unlike warfarin, DOACs do not require regular plasma level monitoring. Objective We investigated whether this simplification in management affects persistence on DOACs vs warfarin. Methods Within two US commercial health insurance databases (MarketScan and Clinformatics™ DataMart), we compared baseline characteristics and evaluated rates of nonpersistence (≥30-day treatment gap or switching) among patients with nonvalvular atrial fibrillation who initiated an oral anticoagulant between October 2010 and September 2015. Results In the larger of the two data sources (MarketScan), we identified 166 690 anticoagulant initiators during the study period. After propensity score (PS) matching, 24 141 dabigatran initiators, 26 066 rivaroxaban, and 12 578 apixaban initiators were included along with the 1:1 matched warfarin initiators. The proportion of patients who were nonpersistent after 12 months was lower for DOAC users (dabigatran 66%, rivaroxaban 60%, apixaban 53%) compared with warfarin users (72%). The same relative ranking was observed in direct comparisons among the DOACs after PS-matching. Findings in Clinformatics DataMart were similar. Conclusion Results from this long-term surveillance program showed that patients who initiated DOACs were more likely to be persistent to therapy compared with those who initiated warfarin. Persistence to anticoagulant therapy was generally poor in commercially insured patients.

The safety of linagliptin with regard to the risk of hospitalization for heart failure (HHF) in patients with type 2 diabetes mellitus (T2DM) as treated in routine care remains of interest. We compared the risk of HHF associated with the initiation of linagliptin vs. other antidiabetic agents. In two large commercial U.S. health insurance datasets (Optum Clinformatics and Truven MarketScan), we identified T2DM patients who initiated linagliptin, sitagliptin, saxagliptin, or sulfonylureas (SU) between 5/2011 and 9/2015 and had no previous Heart Failure (HF) history or HF treatment. We estimated hazard ratios (HR) of HHF in 3 separate propensity score matched cohorts that balanced over 130 baseline characteristics. We combined HRs via a fixed-effects meta-analysis. Mean follow-up was nearly 8 months. Linagliptin initiators had no significant difference in the risk of HHF compared with sitagliptin (HR= 0.83 [95% CI=0.58, 1.20]), saxagliptin (HR= 1.13 [0.74, 1.71]), or SU (HR= 0.71, [0.46, 1.10]). In contrast to high cardiovascular (CV) risk clinical trial populations, in a population of T2DM patients without HF history, aged 57 years on average, we did not find a difference in HHF risk between DPP-4 inhibitors with sufficient certainty. Consistent with prior studies, there may be a reduced HHF risk vs. SU; further evidence is expected from ongoing linagliptin CV outcomes trials. Disclosure E. Patorno: Research Support; Self; National Institute on Aging. Other Relationship; Self; Boehringer Ingelheim GmbH, GlaxoSmithKline plc.. M. Mahesri: None. C. Gopalakrishnan: None. K. Brodovicz: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. A. Meyers: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. D. Bartels: Employee; Self; Boehringer Ingelheim GmbH. S. Schneeweiss: Consultant; Self; WHISCON, LLC. Other Relationship; Self; Aetion, Inc.. Research Support; Self; Genentech, Inc., Bayer AG, Boehringer Ingelheim GmbH, U.S. Food and Drug Administration, Patient-Centered Outcomes Research Institute.

A growing body of observational literature on the association between glucose-lowering treatments and all-cause mortality has been accumulating in recent years. However, many investigations present designs or analyses that inadequately address the methodological challenges involved. We conducted a systematic search with a non-systematic extension to identify observational studies published between 2000 and 2012 that evaluated the effects of glucose-lowering medications on all-cause mortality. We reviewed these studies and assessed the design and analysis methods used, with a focus on their ability to address specific methodological challenges. We described these methodological issues and their potential impact on observed associations, providing examples from the reviewed literature, and suggested possible approaches to manage these methodological challenges. We evaluated 67 publications of observational studies evaluating the association between glucose-lowering treatments and all-cause mortality. The identified methodological challenges included trade-offs associated with the outcome of all-cause mortality, incorrect temporal sequencing in administrative databases, inadequate treatment of time-varying hazards and treatment duration effects, unclear definition of the exposure risk window, improper handling of time-varying exposures, and incomplete accounting for confounding by indication. Most of these methodological challenges may be adequately addressed through the application of appropriate methods. Observational research plays an increasingly important role in assessing the clinical effects of diabetes therapy. The implementation of suitable research methods can reduce the potential for spurious findings, and thus the risk of misleading the medical community about benefits and harms of diabetes therapy.

SummaryThe RE-LY study demonstrated the safety and efficacy of dabigatran relative to warfarin for stroke prevention in non-valvular atrial fibrillation. It is important to further evaluate safety and effectiveness of drugs in routine care. This study used a sequential cohort design with propensity score matching to compare dabigatran with warfarin among patients in two commercial health insurance databases. New users of these anticoagulants were followed from initiation until discontinuation, the end of the study, or the occurrence of a study outcome (primary study outcomes were stroke and major bleeding). Proportional hazards regression was conducted separately within each data source and results were pooled. Among 19,189 matched dabigatran and warfarin initiators (mean age: 68 years, 36 % female), as-treated follow-up (average of 5 months for dabigatran, 4 months for warfarin) identified 62 and 69 strokes, respectively (pooled HR = 0.77; 95 % CI = 0.54 to 1.09), and 354 and 395 major haemorrhages, respectively (HR = 0.75; 0.65 to 0.87). No meaningful heterogeneity was identified across subgroups, but numeric trends suggest more pronounced stroke prevention by dabigatran relative to warfarin among patients age 75+ (HR = 0.57; 0.33 to 0.97) or with < 6 months of use (HR = 0.51; 0.19 to 1.42). Major bleeds were reduced more by dabigatran among patients aged < 55 (HR = 0.51; 0.30 to 0.87) and with CHADS2 < 2 (HR = 0.58; 0.44 to 0.77). In conclusion, in routine care of patients with non-valvular atrial fibrillation, dabigatran treatment resulted in improved health outcomes compared with warfarin.

BACKGROUND Nonrandomized safety and effectiveness studies are often initiated immediately after the approval of a new medication, but patients prescribed the new medication during this period may be substantially different from those receiving an existing comparator treatment. Restricting the study to comparable patients after data have been collected is inefficient in prospective studies with primary collection of outcomes. METHODS We discuss design and methods for evaluating covariate data to assess the comparability of treatment groups, identify patient subgroups that are not comparable, and decide when to transition to a large-scale comparative study. We demonstrate methods in an example study comparing Cox-2 inhibitors during their postmarketing period (1999-2005) with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). RESULTS Graphical checks of propensity score distributions in each treatment group showed substantial problems with overlap in the initial cohorts. In the first half of 1999, >40% of patients were in the region of nonoverlap on the propensity score, and across the study period this fraction never dropped below 10% (the a priori decision threshold for transitioning to the large-scale study). After restricting to patients with no prior NSAID use

Comparing medications in observational settings requires differences in patient characteristics to be accounted for. Propensity score (PS) methods can address these differences, but PS weighting approaches may introduce bias. Within a cohort study of anticoagulant initiators from October 2010 through to December 2012, PS values for dabigatran relative to warfarin were estimated, and study outcomes (stroke or major bleeding) among the cohort were identified. The PS was used to match initiators and results compared with those obtained using inverse probability of treatment weighting (IPTW) and standardized morbidity ratio (SMR) weighting. Hazard ratios (HRs) for study outcomes were estimated using a proportional hazards regression model. There were 23,543 dabigatran and 50,288 warfarin initiators, and matching formed 19,189 pairs (81.5% of dabigatran initiators) which resulted in a pooled stroke HR of 0.77 (95% confidence interval [CI] 0.54–1.09), and a pooled major hemorrhage HR of 0.75 (95% CI 0.65–0.87). The IPTW results for stroke (HR = 0.00; 95% CI 0.00–0.56) and major hemorrhage (HR = 0.08; 95% CI 0.08–0.10) substantially differed, while the SMR-weighted results for stroke (HR = 0.65; 95% CI 0.42–1.03) and major hemorrhage (HR = 0.73; 95% CI 0.61–0.85) differed only slightly from matching. In this example, different applications of the same PS led to substantially different results, a finding that was particularly apparent with IPTW, and this was remedied by truncating extreme weights. If IPTW is used, information regarding the weights applied along with sensitivity analyses could avoid misrepresentation of study results, and would enhance their interpretation.

Inferring causation from non-randomized studies of exposure requires that exposure groups can be balanced with respect to prognostic factors for the outcome. Although there is broad agreement in the literature that balance should be checked, there is confusion regarding the appropriate metric. We present a simulation study that compares several balance metrics with respect to the strength of their association with bias in estimation of the effect of a binary exposure on a binary, count, or continuous outcome. The simulations utilize matching on the propensity score with successively decreasing calipers to produce datasets with varying covariate balance. We propose the post-matching C-statistic as a balance metric and found that it had consistently strong associations with estimation bias, even when the propensity score model was misspecified, as long as the propensity score was estimated with sufficient study size. This metric, along with the average standardized difference and the general weighted difference, outperformed all other metrics considered in association with bias, including the unstandardized absolute difference, Kolmogorov-Smirnov and Levy distances, overlapping coefficient, Mahalanobis balance, and L1 metrics. Of the best-performing metrics, the C-statistic and general weighted difference also have the advantage that they automatically evaluate balance on all covariates simultaneously and can easily incorporate balance on interactions among covariates. Therefore, when combined with the usual practice of comparing individual covariate means and standard deviations across exposure groups, these metrics may provide useful summaries of the observed covariate imbalance.

Aims The introduction of non-VKA oral anticoagulants (NOACs), which differ from the earlier vitamin K antagonist (VKA) treatments, has changed the approach to stroke prevention in atrial fibrillation (AF). GLORIA-AF is a prospective, global registry programme describing the selection of antithrombotic treatment in newly diagnosed AF patients at risk of stroke. It comprises three phases: Phase I, before the introduction of NOACs; Phase II, during the time of the introduction of dabigatran, the first NOAC; and Phase III, once NOACs have been established in clinical practice. Methods and results In Phase I, 1063 patients were eligible from the 1100 enrolled (54.3% male; median age 70 years); patients were from China (67.1%), Europe (EU; 27.4%), and the Middle East (ME; 5.6%). The majority of patients using VKAs had high stroke risk (CHA2DS2-VASc ≥ 2; 86.5%); 13.5% had moderate risk (CHA2DS2-VASc = 1). Vitamin K antagonist use was higher for persistent/permanent AF (47.7%) than that for paroxysmal (23.9%). Most patients in China were treated with antiplatelet agents (53.7%) vs. 27.1% in EU and 28.8% in ME. In China, 25.9% of patients had no antithrombotic therapy, vs. 8.6% in EU and 8.5% in ME. Conclusion Phase I of GLORIA-AF shows that VKAs were mostly used in patients with persistent/permanent (vs. paroxysmal) AF and in those with high stroke risk. Furthermore, there were meaningful geographical differences in the use of VKA therapy in the era before the availability of NOACs, including a much lower use of VKAs in China, where most patients either received antiplatelet agents or no antithrombotic treatment.

GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non-vitamin K antagonist oral anticoagulant (NOAC), became available.This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1.During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients' baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics.Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHAThe baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701).

Background A meta-analysis reported an 8% increased risk of cancer with the use of angiotensin receptor blockers (ARBs), but subsequent meta-analyses and observational studies did not confirm this risk. However, telmisartan comprised 85% of the data in the original meta-analysis. Thus, the objective of this study was to determine whether the use of telmisartan, compared with other ARBs, is associated with an increased risk of cancer. Methods We used the United Kingdom Clinical Practice Research Datalink to assemble a cohort of all patients newly treated with ARBs between 2000 and 2008, and followed until December 2010. Time-dependent cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of cancer associated with telmisartan, compared with other ARBs, adjusted for potential confounders. Secondary analyses assessed the risk with each of the 4 most common cancers (lung, breast, prostate, colorectal). Results The cohort consisted of 62,109 new ARB users, which included 3,438 telmisartan and 58,671 other ARB users. Compared with other ARBs, telmisartan use was not associated with an increased risk of cancer overall (16.3 vs. 15.0 per 1,000 person-years, respectively; adjusted HR: 0.93, 95% CI: 0.81-1.06) or by cancer site (lung, HR: 0.91, 95% CI: 0.55-1.51; breast, HR: 1.28, 95% CI: 0.90-1.82; prostate, HR: 0.79, 95% CI: 0.53-1.18; colorectal, HR: 1.41, 95% CI 0.95-2.10). Conclusions Compared with other ARBs, telmisartan is not associated with an increased risk of cancer. This study provides reassurance as to the short-term safety of telmisartan.

In multimorbidity indices, chronic conditions are often weighted according to their severity or their impact on different outcomes. These weights are mostly developed on the basis of only one study population by using very specific study participants, such as hospital patients. To overcome the limited validity of the indices, mean weights across five population-based studies were calculated according to the impact of diseases on self-reported health status.Individual data was provided from the National Health Interview and Examination Survey (n=1,010), Dortmund Health Study (n=281), Memory and Morbidity in Augsburg Elderly Study (n=385), Survey of Health, Aging and Retirement in Europe Study (n=1,278), and Study of Health in Pomerania Study (n=962). By using logistic regression analysis, odds ratios (ORs) were calculated for reporting a fair or poor health status resulting from one of 10 different chronic conditions compared with a reference group without the specific disease, controlling for age and sex. If the results were homogenous across studies (I(2)40%), significant pooled ORs were considered valid weights for a multimorbidity index.Myocardial infarction has the highest impact on self-reported health status across studies with a pooled OR of 3.9, followed by chronic obstructive pulmonary disease (pooled OR: 3.1). A medium impact was observed for arthrosis, asthma, diabetes mellitus, and osteoporosis.This method provided valid weights for seven chronic conditions.

Background: Dabigatran etexilate is a newer oral anticoagulant developed as an alternative to warfarin for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). Although the efficacy and safety of dabigatran were established in a randomized trial, evaluation of its effects in routine clinical practice is ongoing. Objectives: Quantification of the comparative safety and effectiveness of dabigatran in routine care within two large US commercial health insurance databases (Truven MarketScan and Optum Clinformatics) Methods: Cohort design with propensity score (PS) matching to compare new initiators of dabigatran with warfarin between October 2010 and June 2013. Primary outcomes were stroke and major bleeding. Proportional hazards regression of time to outcome was conducted separately within each data source and results were pooled. Results: There were 22,736 PS matched dabigatran and warfarin initiators with NVAF pooled across data sources (MarketScan 18,726; Optum 4,010). The matching resulted in well balanced cohorts with no individual characteristic (including stroke and bleeding risk factors) having a standardized difference of greater than 0.1. The average follow-up for the as-treated analyses was 5 months for dabigatran and 4 months for warfarin. There were 69 strokes amongst dabigatran initiators and 84 strokes amongst warfarin initiators for a pooled HR of 0.71 (95% CI 0.51 – 0.98) (MarketScan HR = 0.65, 95% CI=0.45-0.93, Clinformatics HR = 1.05, 95% CI = 0.50-2.19). For the outcome of major hemorrhage, there were 429 events amongst dabigatran initiators and 480 events amongst warfarin initiators for a pooled HR of 0.77, 95% CI = 0.68 – 0.88) (MarketScan HR = 0.80, 95% CI = 0.70 - 0.92, Clinformatics HR = 0.55, 95% CI = 0.37 - 0.82). Pooled results in the full cohort were fairly consistent across numerous subgroup and sensitivity analyses, however, comparative conclusions within some subgroups are limited by small numbers and limited follow-up time. Conclusions: Analyses from this ongoing sequential long-term study program suggest a reduced risk of both stroke and major hemorrhage for dabigatran relative to warfarin. Continued follow-up will increase the sample size, permitting greater precision in effect estimates.

Aim: To evaluate which clinical symptoms indicate proven neonatal bacterial infection (NBI) and whether measuring procalcitonin aside from C-reactive protein and interleukin 6 improves sensitivity and specificity in diagnosis. Methods: In a prospective observational study, clinical symptoms and procalcitonin, C-reactive protein and interleukin 6 were simultaneously determined from the 4th day of life in 170 preterm and term neonates at the first time of suspicion of NBI. Proven NBI was defined as a positive culture of otherwise sterile body fluids or radiologically verified pneumonia in combination with elevated inflammatory markers. Results: Fifty-eight (34%) patients were diagnosed with proven late-onset NBI. In case of proven NBI, odds ratio and 95% confidence intervals were 2.64 (1.06–6.54) for arterial hypotension, 5.16 (2.55–10.43) for feeding intolerance and 9.18 (4.10–20.59) for prolonged capillary refill. Sensitivity of combined determination of C-reactive protein (>10 mg/L) and interleukin 6 (>100 pg/mL) was 91.4%, specificity 80.4%, positive predictive value 70.7% and negative predictive value 94.7%. The additional determination of procalcitonin (>0.7 ng/mL) resulted in 98.3%, 65.2%, 58.8% and 98.6%, respectively. Conclusion: Arterial hypotension, feeding intolerance and especially prolonged capillary refill indicate proven neonatal late-onset bacterial infection, even at the time of first suspicion. Additional measurement of procalcitonin does indeed improve sensitivity to nearly 100%, but is linked to a decline in specificity. Nevertheless, in the high-risk neonatal population, additional procalcitonin measurement can be recommended because all infants with NBI have to be identified.

There are limited real world data on the cardiovascular (CV) safety and effectiveness of linagliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4i) approved in the U.S. in May 2011. Within two U.S. claims databases (05/2011-12/2015), we identified three pairwise 1:1 propensity score (PS)-matched

Summary Objectives Although many newer diabetes medications have become available in the last decade, most have not been widely studied in populations with chronic kidney disease under routine care. Linagliptin, a recently marketed dipeptidyl peptidase 4 (DPP‐4) inhibitor, is the only agent in the U.S. that does not require dose adjustment in patients with diabetes mellitus type 2 (T2DM) and renal impairment. We sought to describe baseline kidney function and other key characteristics among patients with diabetes mellitus type 2 (T2DM) initiating linagliptin and other diabetes medications, and to explore prescribing patterns among T2DM patients with moderate to severe renal impairment before and after the launch of linagliptin. Design Using a population‐based cohort study design nested in a large U.S. commercial healthcare dataset linked to laboratory values, we described characteristics of T2DM patients initiating linagliptin and other diabetes medications between May 2011 (launch of linagliptin) and September 2015. We also explored prescribing trends among T2DM patients with moderate to severe renal impairment (ICD‐9 diagnosis code 585.3x‐6x) who initiated linagliptin and other diabetes medications between January 2006 to September 2015 (before and after the launch of linagliptin). Patients We identified 1,174,476 T2DM patients initiating a diabetes medication (28,900 linagliptin initiators) between 05/2011‐09/2015. We also identified 100,847 T2DM patients with moderate to severe renal impairment initiating a diabetes agent between 01/2006‐09/2015. Results and Conclusion Among patients initiating newer diabetes medications between 05/2011‐09/2015, those initiating linagliptin had the highest prevalence of moderate to severe renal impairment, suggesting preferential prescribing in routine care. DPP‐4 inhibitors overall were among the most frequently chosen agents among T2DM patients with moderate to severe renal impairment between 01/2006‐09/2015. Further investigation of the safety and effectiveness of DPP‐4 inhibitors in routine care of T2DM patients with renal impairment is needed to either corroborate or discourage current prescribing patterns.

Background: Early diagnosis of necrotising enterocolitis (NEC) is difficult but essential for timely therapy. The diagnostic hallmarks and specific radiological signs for NEC are pneumatosis intestinalis (PI) and portal venous gas (PVG), but PVG in abdominal ultrasound (PVG-US) has been proposed as an effective tool in the diagnosis of NEC as well. Objective: To prospectively assess the value of PVG-US for the diagnosis of NEC. Methods: The study screened 352 neonates for PVG-US (n = 796 routine examinations) and performed 48 additional screenings in 34/352 neonates with suspected (stage I, n = 28) or definite NEC (stage ⩾II, n = 20). Sensitivity and specificity of PVG-US for detection of NEC were computed by using NEC stage ⩾II as the reference standard. Results: PVG-US was only present in cases of suspected or definite NEC. The study observed PVG-US in 4/28 NEC stage I and in 9/20 NEC stage ⩾II episodes corresponding to a 86% specificity and a 45% sensitivity for diagnosis of NEC stage ⩾II. However, 7/20 patients with NEC stage ⩾II showed intraoperative findings other than NEC and another 3/20 infants presented with radiologically unspecific intestinal dilatation. None of these 10 infants had detectable PVG-US. Thus, with application of specific radiological signs the sensitivity of PVG-US for diagnosis of NEC stage ⩾II increased to 90%. Conclusion: Screening for PVG-US is a useful, easy and quick bedside test with a high specificity for NEC. Moreover, these results question the value of the Walsh criteria in the diagnosis of NEC.

OBJECTIVES Inflammation plays a role in prematurity, in neonatal disorders of the brain, lung, eye, bowel, and in developmental disability among preterm infants. We initiated a pilot study in preterm children to determine the prevalence of single nucleotide polymorphisms (SNPs) in the infection/inflammation-associated genes for interleukin (IL)-10 (- 1082 G/A), IL-1beta (+ 3953 C/T), tumor necrosis factor (TNF)-alpha (- 308 G/A) and toll-like receptor 4 (TLR-4) (Asp299Gly) and whether these SNPs affect the risk for neonatal disorders. STUDY DESIGN We genotyped 73 children >/= 2 years of age whose gestational age at birth was < 32 weeks, and explored the associations between genotypes and neonatal disorders and developmental status at age 2 + years. RESULTS Infants homozygous for the high IL-10 producer - 1082 G-allele (n = 15) were significantly less likely to develop ultrasound-defined periventricular echodensities. A non-significant, but prominent, risk reduction for bronchopulmonary dysplasia, high-grade retinopathy, cerebral palsy, and developmental delay at age 2 + years was present. Polymorphisms in the IL-1beta, TNF-alpha, and TLR-4 genes were too infrequent in our pilot sample to allow for reasonable analysis. CONCLUSION Infants homozygous for the IL-10 high producer - 1082 G allele might be at reduced risk for prematurity-associated disorders.

BACKGROUND. Very low birth weight infants (METHODS. We analyzed population-based data from a quality assurance program in Lower Saxony (Germany). Perinatal data for almost all very low birth weight infants born in 1991 to 1999 (n = 7745) were available. Analyses were restricted to infants born at 24 to 30 weeks (n = 4379). Data validation procedures, univariate data analyses, and logistic regression models based on general estimating equations were performed.RESULTS. Neonatal mortality among infants admitted to NICUs was 12.2% in small NICUs and 10.2% in large NICUs. The mortality rate in small NICUs was increased significantly. Compared with infants from large delivery hospitals (>1000 births per year) and large NICUs, the adjusted odds ratio was 1.94 for neonates for whom both units were small, 1.75 for those from large delivery units but small neonatal units, and 1.16 for those for whom only the NICU was large. Stratification according to gestational age revealed the greatest impact on mortality for infants of CONCLUSIONS. Results suggest that creating larger perinatal centers may improve perinatal health care. The volume of the NICU was associated more strongly with 28-day mortality than was the volume of the delivery hospital, and it had the largest impact on survival for infants of

Cranial ultrasonography has been used to identify brain injury in preterm neonates for more than two decades. More recently, magnetic resonance imaging has been used to evaluate brain development and pathology in these infants. In this review we describe how well findings from these two imaging modalities agree with histology findings and neuro-developmental outcome. In addition, we discuss studies comparing ultrasound and magnetic resonance imaging findings.

The relationships among bronchopulmonary dysplasia (BPD), brain white matter damage (WMD) and cerebral palsy (CP) are far from simple. Apparently, BPD and WMD are not associated, while BPD and CP are. The most likely explanation for this paradox is that ultrasound imaging does not identify all the WMD that might lead to CP (‘tip-of-the-iceberg effect’). We discuss further methodological inconsistencies, etiological peculiarities related to antenatal infection/inflammation, and intervention-related issues. In particular, we expand on the multiple-hit scenario in the etiology of BPD and offer support for the hypothesis that it is not lung disease, but factors associated with lung disease (e.g. postnatal steroid exposure) that increase the risk for developmental disability in childhood.

Background: Current guidelines recommend long-term oral anticoagulation (OAC) for stroke prevention in patients with non-valvular atrial fibrillation (AF), at risk for stroke. Treatment discontinuation rates are high in patients treated with vitamin K antagonists (VKA), with only half remaining on

Background Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting 1% to 2% of the population and raising the risk of stroke 5-fold. Until recently, the only treatment choices for stroke prevention in patients with AF have been vitamin K antagonists (VKA) or antiplatelet drugs. With approval of novel oral anticoagulants (NOACs) antithrombotic treatment, patterns are changing. The Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation is designed to investigate patient characteristics influencing choice of antithrombotic treatment of stroke prevention in patients with nonvalvular AF and to collect data on outcomes of antithrombotic therapy in clinical practice. Methods The GLORIA-AF is a large, international, observational registry involving patients with newly diagnosed nonvalvular AF at risk for stroke, enrolling up to 56,000 patients in nearly 50 countries. We will collect and analyze data from routine care using an inception cohort design. Phase I includes patients before approval of NOACs. Phase II, beginning early after approval of dabigatran, monitors dabigatran safety and addresses potential channeling across treatment options based on propensity scoring to assess comparability of baseline characteristics of patients treated with dabigatran or VKA. Phase III entails analysis of large treatment groups, adjusting for differences in propensity score, to provide information about the relative effectiveness and safety of NOACs and VKA in routine clinical care. Conclusions Novel features of this registry program will add data from clinical practice to those from randomized trials to expand knowledge of antithrombotic treatment in patients with AF.