Design and rationale of Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation: a global registry program on long-term oral antithrombotic treatment in patients with atrial fibrillation.

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.

Population-based cohort study of warfarin-treated patients with atrial fibrillation: incidence of cardiovascular and bleeding outcomes.

OBJECTIVES: Atrial fibrillation (AF) is the most common cardiac rhythm disorder with a significant health burden. The aim of this study was to characterise patients with recently diagnosed AF and to estimate the rates of comorbidities and outcome events requiring hospitalisation in routine clinical practice. DESIGN: Pharmacoepidemiological cohort study using observational data. METHODS/SETTING: This study included 16 513 patients with a first diagnosis of AF between 1 January 2005 and 28 February 2010 (newly diagnosed patients) using data from the UK Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics (HES) and the Office for National Statistics mortality data. Exposure was stratified by vitamin K antagonist (VKA) exposure (non-use, current, recent and past exposure) based on prescriptions and/or international normalised ratio measurements, and followed for outcome events of interest based on diagnosis codes in the databases, that is, vascular outcomes, bleeding events and others. The main focus of the study was on outcome events requiring hospitalisation using the HES data. RESULTS: The incidence of vascular outcome hospitalisations (myocardial infarction (MI), stroke or systemic arterial peripheral embolism) was 3.8 (95% CI 3.5 to 4.0)/100 patient-years. The incidence of stroke was 0.9 (0.8 to 1.1) during current VKA exposure, 2.2 (1.6 to 2.9) for recent, 2.4 (1.9 to 2.9) for past and 3.4 (3.1 to 3.7) during non-use. MI incidence was 0.7 (0.6 to 0.9) for current VKA exposure, 0.7 (0.4 to 1.2) for recent, 1.1 (0.8 to 1.5) for past and 1.9 (1.7 to 2.1) during non-use. The incidence of bleeding event hospitalisations was 3.8 (3.4 to 4.2) for current VKA exposure, 4.5 (3.7 to 5.5) for recent, 2.7 (2.2 to 3.3) for past and 2.9 (2.6 to 3.2) during non-use; 38% of intracranial bleeds and 6% of gastrointestinal bleeds were fatal. CONCLUSIONS: This population-based study from recent years provides a comprehensive characterisation of newly diagnosed patients with AF and incidence estimates of common outcomes with a focus on hospitalised events stratified by VKA exposure. This study will help to place future data on new oral anticoagulants into perspective.

Metrics for covariate balance in cohort studies of causal effects.

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 Lévy 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.

Non-response bias in a surveillance program for asbestos-related lung cancer.

OBJECTIVES: In a cohort study non-response might lead to a biased selection of cohort members and may affect the validity and reliability of the study outcome. To detect the possible effects of a non-response bias on study results, we evaluated the reasons for non-participation and the differences of respondents and non-respondents in a health surveillance program for power industry workers, formerly exposed to asbestos. METHODS: A cohort of former power plant workers was formed to participate in an early detection program for lung cancer. We evaluated the results of 1,019 individuals (mean age 66 yr), of which 839 took part in at least one examination, 180 refused to participate or did not respond. To obtain the reasons for non-response, we interviewed the cohort members by telephone or we requested them by mail to complete and return a brief questionnaire. Further sources of information were the communal registration offices and local health offices. RESULTS: The main reasons for non-participation were refusal (35%), illness (23.3%), death (16.7%) and difficulties with traveling (13.3%). It was impossible to make contact with or obtain an explanation from 11.7%. In a logistic regression model we demonstrated that advanced age and a long travel distance from the study center negatively affected the participation rate (p<0.001). There was no difference between respondents and non-respondents regarding prevalence (p=0.559) and incidence of lung cancer (p=0.882). CONCLUSION: We concluded that in our cohort non-participation did not cause a selection bias in terms of lung cancer rates.

Retrospective exposure assessment to airborne asbestos among power industry workers.

BACKGROUND: A method of individually assessing former exposure to asbestos fibres is a precondition of risk-differentiated health surveillance. The main aims of our study were to assess former levels of airborne asbestos exposure in the power industry in Germany and to propose a basic strategy for health surveillance and the early detection of asbestos related diseases. METHODS: Between March 2002 and the end of 2006, we conducted a retrospective questionnaire based survey of occupational tasks and exposures with airborne asbestos fibres in a cohort of 8632 formerly asbestos exposed power industry workers. The data on exposure and occupation were entered into a specially designed computer programme, based on ambient monitoring of airborne asbestos fibre concentrations. The cumulative asbestos exposure was expressed as the product of the eight-hour time weighted average and the total duration of exposure in fibre years (fibres/cubic centimetre-years). RESULTS: Data of 7775 (90% of the total) participants working in installations for power generation, power distribution or gas supply could be evaluated. The power generation group (n = 5284) had a mean age of 56 years, were exposed for 20 years and had an average cumulative asbestos exposure of 42 fibre years. The occupational group of "metalworkers" (n = 1600) had the highest mean value of 79 fibre years. The corresponding results for the power distribution group (n = 2491) were a mean age of 45 years, a mean exposure duration of 12 years and an average cumulative asbestos exposure of only 2.5 fibre years. The gas supply workers (n = 512) had a mean age of 54 years and a mean duration of exposure of 15 years. CONCLUSIONS: While the surveyed cohort as a whole was heavily exposed to asbestos dust, the power distribution group had a mean cumulative exposure of only 6% of that found in the power generation group. Based on the presented data, risk-differentiated disease surveillance focusing on metalworkers and electricians from the power generating industry seems justified. That combined with a sensitive examination technique would allow detecting asbestos related diseases early and efficiently.

Effect of different saline chaser volumes and flow rates on intravascular contrast enhancement in CT using a circulation phantom.

PURPOSE: To evaluate the influence of different saline chaser volumes and different saline chaser flow rates on the intravascular contrast enhancement in MDCT. MATERIALS AND METHODS: In a physiological flow phantom contrast medium (120 ml, 300 mgI/ml, Ultravist 300) was administered at a flow rate of 6 ml/s followed by different saline chaser volumes (0, 30, 60 and 90 ml) at the same injection rate or followed by a 30-ml saline chaser at different injection rates (2, 4, 6 and 8 ml/s). Serial CT-scans at a level covering the pulmonary artery, the ascending and the descending aorta replica were obtained. Time-enhancement curves were computed and both pulmonary and aortic peak enhancement and peak time were determined. RESULTS: Compared to contrast medium injection without a saline chaser the pushing with a saline chaser (30, 60, and 90 ml) resulted in a statistically significant increased pulmonary peak enhancement (all p=0.008) and prolonged peak time (p=0.032, p=0.024 and p=0.008, respectively). Highest aortic peak enhancement values were detected for a saline chaser volume of 30 ml. A saline chaser flow rate of 8 ml/s resulted in the highest pulmonary peak enhancement values compared to flow rates of 2, 4 and 6 ml/s (all p=0.008). Aortic peak enhancement showed the highest values for a flow rate of 6 ml/s. CONCLUSION: A saline chaser volume of 30 ml and an injection rate of 6 ml/s are sufficient to best improve vascular contrast enhancement in the pulmonary artery and the aorta in MDCT.

Influence of temperature on the positive inotropic effect of levosimendan, dobutamine and milrinone.

BACKGROUND AND OBJECTIVE: Patients in cardiac surgery and critically ill patients often demonstrate either hypothermia or fever. In addition, owing to heart failure, they frequently require inotropic support. The relative effectiveness of modern inotropic agents at various temperatures has not yet been evaluated. Therefore, we investigated the influence of levosimendan, dobutamine and milrinone on the contractile response of myocardial trabeculae at various temperatures. METHODS: A total of 120 guinea pig ventricular trabeculae were placed in oxygenated 4-(2-hydroxyethyl)-1-piperazineethanesulphonic acid (HEPES) buffer, stimulated at a frequency of 1.3 Hz and randomly assigned to a temperature of 31 degrees C, 34 degrees C, 37 degrees C or 40 degrees C. Concentrations of all substances were increased stepwise from 10(-9) to 10(-5) mol l(-1) (milrinone up to 10(-4) mol l(-1)). Maximum developed force, time to peak tension, Tsystolic(50%) and Tdiastolic(50%) were continuously recorded. RESULTS: All agents showed a dose-dependent positive inotropic effect (P < 0.0001 for all). Levosimendan acted at every temperature as a positive inotrope (P = 0.0643). Dobutamine-related inotropy showed a clear trend towards temperature dependence, although statistical evaluation did not prove this (P = 0.0624). Milrinone-related inotropy was abolished at 31 degrees C and 34 degrees C, and temperature dependence was significant (P < 0.0001). Hypothermia induced a positive inotropic effect. CONCLUSION: Our results suggest no modulation of levosimendan-induced inotropy under the experimental temperatures tested. This observation is possibly due to its Ca2+-sensitizing mechanism, which might not be influenced by temperature-related changes in intracellular Ca2+ levels. In contrast, the inotropic effect of cyclic AMP-coupled dobutamine and milrinone is suppressed under hypothermia-related interaction with intracellular Ca2+ homeostasis. Hence, levosimendan might prove to be the preferred inotropic drug in hypothermic patients.

Risk factors for cardiovascular calcifications in non-diabetic Caucasian haemodialysis patients.

BACKGROUND/AIMS: Dialysis patients display an increased mortality which is associated with cardiovascular calcifications. Diabetes mellitus and ethnicity are known factors that affect the extent of cardiovascular calcifications. However, most studies have investigated mixed cohorts with diabetics and/or mixed ethnicity. METHODS: Cardiovascular calcifications were assessed in non-diabetic Caucasian haemodialysis patients by the semiquantitative Adragao calcification score (X-ray pelvis and hands) and a novel composite calcification score encompassing the Adragao score as well as calcifications detected by X-ray of the fistula arm, echocardiography of heart valves and carotid ultrasound. RESULTS: Using multivariate analysis, age, male gender, dialysis vintage, lower Kt/V, calcium-phosphate product, smoking and high-sensitivity CRP were independent risk factors for cardiovascular calcifications as assessed by the Adragao or the composite score. Pulse wave velocity was independently related to both calcification scores. Body mass index, cholesterol, triglycerides, iPTH and serum levels of fetuin-A and uncarboxylated matrix Gla protein were not associated with cardiovascular calcifications. CONCLUSIONS: In our cohort of non-diabetic Caucasian haemodialysis patients, age, male gender, dialysis vintage, smoking, calcium-phosphate product, high-sensitivity CRP and lower Kt/V were independent risk factors for cardiovascular calcifications. Whether lowering the calcium-phosphate product and increasing dialysis efficiency can reduce cardiovascular calcifications in dialysis patients remains to be determined.

Image fusion in dual energy computed tomography: effect on contrast enhancement, signal-to-noise ratio and image quality in computed tomography angiography.

OBJECTIVE: The aim of this study was to evaluate the influence of different weighting factors on contrast enhancement, signal-to-noise ratio (SNR), and image quality in image fusion in dual energy computed tomography (DECT) angiography. MATERIAL AND METHODS: Fifteen patients underwent a CT angiography of the aorta with a SOMATOM Definition Dual Source CT (DSCT; Siemens, Forchheim, Germany) in dual energy mode (DECT) (tube voltage: 80 and 140 kVp; tube current: 297 eff. mA and 70 eff. mA; collimation, 14 x 1.2 mm). Raw data were reconstructed using a soft convolution kernel (D30f). Fused images were calculated using a spectrum of weighting factors (0.0, 0.1, 0.3, 0.5, 0.7, 0.9, and 1.0) generating different ratios between the 80- and 140-kVp images (eg, factor 0.5 corresponds to 50% image information from the 140- and the 80-kVp image). Both CT values and SNR were measured in the descending aorta (levels of celiac trunk, renal arteries, and aortic bifurcation), in the right and left common iliac artery and in paraaortal fat. Image quality was evaluated using a 5-point grading scale. Results were compared using paired t-tests and nonparametric paired Wilcoxon tests. RESULTS: Statistically significant increases in mean CT values were seen in vessels when increasing weighting factors were used (all P

Supportive Versus Immunosuppressive Therapy of Progressive IgA nephropathy (STOP) IgAN trial: rationale and study protocol.

INTRODUCTION: The best treatment of IgA nephropathy (IgAN) is currently not well defined. The Supportive Versus Immunosuppressive Therapy of Progressive IgA Nephropathy (STOP IgAN) trial aims to answer if, in IgAN patients, an immunosuppressive treatment is more effective than a supportive treatment. METHODS: In a randomized prospective multicenter study (www.clinicaltrials.gov, NCT00554502), we will treat 148 patients at risk for progressive IgA nephropathy following a 6-month run-in phase, in 2 groups: (group a) supportive treatment: patients with a persistent proteinuria >0.75 g/day will receive a maximized therapy to reduce blood pressure and urinary protein loss using angiotensin-converting enzyme inhibitors and AT1 blockers, statins, dietary counseling for a low-sodium and low-protein diet and education/intervention programs to stop smoking. (group b) immunosuppressive treatment: in addition to the identical treatment of group a, patients will receive treatment with steroids (glomerular filtration rate [GFR] > or =60 ml/min) or steroids plus cyclophosphamide/azathioprine (GFR <60 ml/min). Study end points are the complete remission of the disease and the individual degree of renal functional loss. If the immunosuppressive therapy shows a superior efficacy with respect to prevention of renal failure, the potentially higher therapy cost and risk might be justified. Finally, our trial can serve as a model for various other types of glomerulonephritis, for which such trials are very difficult to perform, given their infrequency.

The risk to develop a recurrence of a gastric cancer-is it independent of time?

BACKGROUND AND AIMS: Recurrence is the main reason for early death of cancer patients. Therefore, survival curves are regarded as crucial tools for clinicians to evaluate therapies and to estimate the patients' prognosis. Current models for the development of recurrence are based on the assumption of a residual cancer cell burden after therapy. Accordingly, in assumption of an exponential cell growth of the cancer cells an S-shaped decline of the survival curve is expected with earlier onset in case of advanced cancer and a later manifestation in case of little residual tumour. However, many survival curves do not reflect any S-shaped configuration and thus may question the current concept. MATERIALS AND METHODS: To test, whether the incidence for developing a recurrence may be considered as remaining constant over time, we analysed survival data of 446 patients with gastric cancer, operated from 1975-2001 in the Surgical Department of the RWTH Aachen. RESULTS: All survival curves, even after sub-grouping according to UICC stage, show a monotonous decline without any apparent S-shape. The impact of TNM and UICC stage to predict the survival in patients is estimated by Cox regression, for estimation the risk for death a logistic regression is performed. Whereas the presence of metastasis lowers the prognosis significantly with a hazard ratio of 1.57 and an odds ratio of 7.56, respectively, a significant relevance for the UICC stage, the tumour size or the lymph node status cannot be proven. Furthermore, the two assumptions: (1) that 20% of patients who are still alive after 5 years have been cured, and (2) that the remainder develop a recurrence in constantly 7.3% per month, are able to configure the survival curve almost precisely (correlation coefficient between calculated and observed survival rate r > 0.99). CONCLUSION: The absence of any S-shaped survival curve configuration is not in accordance with the focus on residual tumour clones with its exponential growth as the decisive process for recurrence development. In contrast, the monotonous decline of surviving patients is best reflected by a constant incidence of recurrence. The (time) constancy of the recurrence incidence encourages the view of recurrent cancer as a chronic problem of a carcinogenic environment. Furthermore, it supports new anticancer therapies which rather targets cell regulation and immunology instead of acting cytotoxic.