Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Improved risk stratification of patients with atrial fibrillation: an integrated GARFIELD-AF tool for the prediction of mortality, stroke and bleed in patients with and without anticoagulation.

OBJECTIVES: To provide an accurate, web-based tool for stratifying patients with atrial fibrillation to facilitate decisions on the potential benefits/risks of anticoagulation, based on mortality, stroke and bleeding risks. DESIGN: The new tool was developed, using stepwise regression, for all and then applied to lower risk patients. C-statistics were compared with CHA2DS2-VASc using 30-fold cross-validation to control for overfitting. External validation was undertaken in an independent dataset, Outcome Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). PARTICIPANTS: Data from 39 898 patients enrolled in the prospective GARFIELD-AF registry provided the basis for deriving and validating an integrated risk tool to predict stroke risk, mortality and bleeding risk. RESULTS: The discriminatory value of the GARFIELD-AF risk model was superior to CHA2DS2-VASc for patients with or without anticoagulation. C-statistics (95% CI) for all-cause mortality, ischaemic stroke/systemic embolism and haemorrhagic stroke/major bleeding (treated patients) were: 0.77 (0.76 to 0.78), 0.69 (0.67 to 0.71) and 0.66 (0.62 to 0.69), respectively, for the GARFIELD-AF risk models, and 0.66 (0.64-0.67), 0.64 (0.61-0.66) and 0.64 (0.61-0.68), respectively, for CHA2DS2-VASc (or HAS-BLED for bleeding). In very low to low risk patients (CHA2DS2-VASc 0 or 1 (men) and 1 or 2 (women)), the CHA2DS2-VASc and HAS-BLED (for bleeding) scores offered weak discriminatory value for mortality, stroke/systemic embolism and major bleeding. C-statistics for the GARFIELD-AF risk tool were 0.69 (0.64 to 0.75), 0.65 (0.56 to 0.73) and 0.60 (0.47 to 0.73) for each end point, respectively, versus 0.50 (0.45 to 0.55), 0.59 (0.50 to 0.67) and 0.55 (0.53 to 0.56) for CHA2DS2-VASc (or HAS-BLED for bleeding). Upon validation in the ORBIT-AF population, C-statistics showed that the GARFIELD-AF risk tool was effective for predicting 1-year all-cause mortality using the full and simplified model for all-cause mortality: C-statistics 0.75 (0.73 to 0.77) and 0.75 (0.73 to 0.77), respectively, and for predicting for any stroke or systemic embolism over 1 year, C-statistics 0.68 (0.62 to 0.74). CONCLUSIONS: Performance of the GARFIELD-AF risk tool was superior to CHA2DS2-VASc in predicting stroke and mortality and superior to HAS-BLED for bleeding, overall and in lower risk patients. The GARFIELD-AF tool has the potential for incorporation in routine electronic systems, and for the first time, permits simultaneous evaluation of ischaemic stroke, mortality and bleeding risks. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier for GARFIELD-AF (NCT01090362) and for ORBIT-AF (NCT01165710)

Two-year outcomes of patients with newly diagnosed atrial fibrillation: results from GARFIELD-AF.

AIMS: The relationship between outcomes and time after diagnosis for patients with non-valvular atrial fibrillation (NVAF) is poorly defined, especially beyond the first year. METHODS AND RESULTS: GARFIELD-AF is an ongoing, global observational study of adults with newly diagnosed NVAF. Two-year outcomes of 17 162 patients prospectively enrolled in GARFIELD-AF were analysed in light of baseline characteristics, risk profiles for stroke/systemic embolism (SE), and antithrombotic therapy. The mean (standard deviation) age was 69.8 (11.4) years, 43.8% were women, and the mean CHA2DS2-VASc score was 3.3 (1.6); 60.8% of patients were prescribed anticoagulant therapy with/without antiplatelet (AP) therapy, 27.4% AP monotherapy, and 11.8% no antithrombotic therapy. At 2-year follow-up, all-cause mortality, stroke/SE, and major bleeding had occurred at a rate (95% confidence interval) of 3.83 (3.62; 4.05), 1.25 (1.13; 1.38), and 0.70 (0.62; 0.81) per 100 person-years, respectively. Rates for all three major events were highest during the first 4 months. Congestive heart failure, acute coronary syndromes, sudden/unwitnessed death, malignancy, respiratory failure, and infection/sepsis accounted for 65% of all known causes of death and strokes for <10%. Anticoagulant treatment was associated with a 35% lower risk of death. CONCLUSION: The most frequent of the three major outcome measures was death, whose most common causes are not known to be significantly influenced by anticoagulation. This suggests that a more comprehensive approach to the management of NVAF may be needed to improve outcome. This could include, in addition to anticoagulation, interventions targeting modifiable, cause-specific risk factors for death. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes.

Abstract BACKGROUND: The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown. METHODS: We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. RESULTS: In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups. CONCLUSIONS: Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 .)

Health-based guidelines for indoor air

Dit rapport geeft gezondheidkundige advieswaarden voor een groot aantal chemische agentia die in de woningen kunnen voorkomen, alsmede voor een aantal fysische factoren. In de praktijk bestaat behoefte aan dergelijke advieswaarden, omdat er voor veel agentia geen waarden beschikbaar zijn om de kwaliteit van het binnenmilieu van woningen aan te toetsen. Bij het vaststellen van de lijst van agentia waarvoor waarden dienden te worden afgeleid, is uitgegaan van stoffen of produkten die veel binnenshuis worden gebruikt of die vanuit de praktijk regelmatig als probleem naar voren komen. Voor de (chemische) stoffen geldt dat alleen blootstelling via inhalatie in ogenschouw is genomen. Voor de andere agentia is de bijbehorende wijze van blootstelling beoordeeld. De 'gezondheidkundige advieswaarde' is hier gedefinieerd als het Maximaal Toelaatbaar Risico (MTR). Voor het compartiment lucht wordt dit meestal aangeduid als de Toelaatbare Concentratie in Lucht (TCL). Voor stoffen met drempelwaarde is dit de concentratie die bij levenslange blootstelling (70 jaar, 365 dagen/jaar en 24 uur per dag) geen effect op de gezondheid heeft. Bij de afleiding wordt rekening gehouden met risicogroepen als zieken, zwangeren, ouderen of kinderen. Van genotoxisch werkende carcinogenen wordt aangenomen dat er geen drempelwaarde is waaronder geen effecten optreden: elke dosis, hoe gering ook, is verbonden met een zeker risico op kanker. Voor deze categorie stoffen is het MTR gedefinieerd als 1 geval (van kanker) per 1.000.000 blootgestelden per jaar of 1 op 10.000 gedurende een heel leven. Voor de agentia waarvoor geen advieswaarde kon worden afgeleid (onder andere biologische agentia) wordt uitgebreid beschreven welke informatie dan wel beschikbaar is en waarom er geen gezondheidkundige advieswaarde is vast te stellen. In principe zijn de advieswaarden gericht op woningen, maar ze zijn ook toepasbaar op andere locaties waar mensen langdurig verblijven (zoals kantoren en scholen). De gezondheidkundige advieswaarden hebben geen wettelijke status, maar kunnen dienen als uitgangspunt voor beleid ten aanzien van het binnenmilieu.Health-based guidelines for chemical and some physical substances in dwellings were derived and summarised in this report. Substances were selected on the basis of product use in dwellings or the fact they have proven to cause problems in different indoor environments. For chemical substances, exposure via inhalation was taken into account. For other agents, the corresponding route of exposure was considered. No guidelines for biological agents could be derived on the basis of current knowledge, as outlined in this document. This conclusion also applies to other agents, like non-ionising radiation and moisture. ssible Risk (MRP), according to Dutch Environmental Policy. For substances with a threshold, this refers to a lifetime (70 years, 365 days per year and 24 hrs per day) concentration that will not cause health effects (even in susceptible groups). The MPR of substances without a threshold (carcinogens) is defined as one case (of cancer) per 1 million exposed persons per year or one case per 10,000 during a lifetime. The guidelines here are aimed at dwellings, but could also be applied to other indoor environments where people spend considerable time (schools, offices). Although the guidelines are not laid down by law, they could be used as a starting point for doing so at a later date.VROM-Inspecti

Health-based guidelines for indoor air

Health-based guidelines for chemical and some physical substances in dwellings were derived and summarised in this report. Substances were selected on the basis of product use in dwellings or the fact they have proven to cause problems in different indoor environments. For chemical substances, exposure via inhalation was taken into account. For other agents, the corresponding route of exposure was considered. No guidelines for biological agents could be derived on the basis of current knowledge, as outlined in this document. This conclusion also applies to other agents, like non-ionising radiation and moisture. ssible Risk (MRP), according to Dutch Environmental Policy. For substances with a threshold, this refers to a lifetime (70 years, 365 days per year and 24 hrs per day) concentration that will not cause health effects (even in susceptible groups). The MPR of substances without a threshold (carcinogens) is defined as one case (of cancer) per 1 million exposed persons per year or one case per 10,000 during a lifetime. The guidelines here are aimed at dwellings, but could also be applied to other indoor environments where people spend considerable time (schools, offices). Although the guidelines are not laid down by law, they could be used as a starting point for doing so at a later date.Dit rapport geeft gezondheidkundige advieswaarden voor een groot aantal chemische agentia die in de woningen kunnen voorkomen, alsmede voor een aantal fysische factoren. In de praktijk bestaat behoefte aan dergelijke advieswaarden, omdat er voor veel agentia geen waarden beschikbaar zijn om de kwaliteit van het binnenmilieu van woningen aan te toetsen. Bij het vaststellen van de lijst van agentia waarvoor waarden dienden te worden afgeleid, is uitgegaan van stoffen of produkten die veel binnenshuis worden gebruikt of die vanuit de praktijk regelmatig als probleem naar voren komen. Voor de (chemische) stoffen geldt dat alleen blootstelling via inhalatie in ogenschouw is genomen. Voor de andere agentia is de bijbehorende wijze van blootstelling beoordeeld. De 'gezondheidkundige advieswaarde' is hier gedefinieerd als het Maximaal Toelaatbaar Risico (MTR). Voor het compartiment lucht wordt dit meestal aangeduid als de Toelaatbare Concentratie in Lucht (TCL). Voor stoffen met drempelwaarde is dit de concentratie die bij levenslange blootstelling (70 jaar, 365 dagen/jaar en 24 uur per dag) geen effect op de gezondheid heeft. Bij de afleiding wordt rekening gehouden met risicogroepen als zieken, zwangeren, ouderen of kinderen. Van genotoxisch werkende carcinogenen wordt aangenomen dat er geen drempelwaarde is waaronder geen effecten optreden: elke dosis, hoe gering ook, is verbonden met een zeker risico op kanker. Voor deze categorie stoffen is het MTR gedefinieerd als 1 geval (van kanker) per 1.000.000 blootgestelden per jaar of 1 op 10.000 gedurende een heel leven. Voor de agentia waarvoor geen advieswaarde kon worden afgeleid (onder andere biologische agentia) wordt uitgebreid beschreven welke informatie dan wel beschikbaar is en waarom er geen gezondheidkundige advieswaarde is vast te stellen. In principe zijn de advieswaarden gericht op woningen, maar ze zijn ook toepasbaar op andere locaties waar mensen langdurig verblijven (zoals kantoren en scholen). De gezondheidkundige advieswaarden hebben geen wettelijke status, maar kunnen dienen als uitgangspunt voor beleid ten aanzien van het binnenmilieu

Erythemal irradiances of filtered ultraviolet radiation

A spectrum evaluator (3cm x 3cm) employing four passive dosimeters has been used to evaluate the time averaged spectrum to allow calculation of the erythemal exposures resulting from the predominantly UVA component of filtered solar ultraviolet radiation. An exposure interval of approximately 20 minutes to autumn and spring sunshine was required for the spectrum evaluator to allow evaluation of the filtered source spectrum. For a clear spring day an erythemal exposure of 0.85 MED to a horizontal plane and 0.38 to a vertical plane over a six hour period was measured within a glass enclosure. For a partially cloudy day six weeks later, these were 0.89 MED and 0.44 MED for the horizontal and the vertical planes respectively. The exposure is predominantly due to the UVA component of the solar radiation. The ratios of the filtered to the unfiltered erythemal exposures within and outside the enclosure respectively ranged from 0.08 to 0.18 throughout the two days

Gezondheidkundige advieswaarden binnenmilieu

Chemische stoffen, biologische agentia en fysische factoren zoals geluid en straling kunnen de gezondheid schade toebrengen. Gezondheidkundige advieswaarden voor het binnenmilieu geven aan in hoeverre de bewoners deze agentia binnenshuis kunnen verdragen. Zij worden vooral gebruikt om de kwaliteit van het binnenmilieu te beoordelen. Deze gezondheidskundige advieswaarden kunnen niet alleen voor woningen worden gebruikt maar ook voor kantoren of scholen, plaatsen waar mensen langere tijd binnen verblijven. Zij hebben geen wettelijke status, maar kunnen wel helpen de kwaliteit van het binnenmilieu te verbeteren.Exposure to chemicals, biological agents and physical factors, such as noise and radiation, can be harmful to human health. Health-based guidelines for indoor environments establish the tolerance levels of residential dwellers to these environmental stressors. The primary aim of the guidelines is to enable meaningful assessment of the indoor environment. The guidelines are intended for residential dwellings but could also be applied to public indoor environments, such as schools and offices. Although the guidelines are not laid down by law, they provide the basis for future indoor environment policy.VRO

Effect van UV-straling op de weerstand tegen infectieziekten

Recent studies on the immunosuppressive effects of UVR and the related resistance to infections in humans are presented. The waveband dependency of trans-to-cis isomerisation of urocanic acid in the stratum corneum and the role of DNA damage in UVR-induced erythema and immunosuppression were investigated to further elucidate the underlying mechanisms. Furthermore, human experimental studies on UVR-induced immunomodulation were performed. It appeared that the doses needed to suppress various immune parameters in humans (e.g. NK-activity, contact hypersensitivity) were higher than those needed in experiments in rodents. Still, extrapolation of experimental animal data to the human situation showed that UVR may impair the resistance to different systemic infections at relevant outdoor doses. In observational human studies we aimed to substantiate the relevance of UVR for infections in humans. It was shown that sunny season was associated with a slightly retarded but clinically non-relevant antibody response to hepatitis B vaccination. Furthermore, sunny season appeared to be associated with a small decline in the number of CD4+ T-helper cells in a cohort of HIV infected persons and a higher recurrence of herpes simplex and herpes zoster in a cohort of renal transplant recipients. However, in a study among young children a higher exposure to solar UVR was associated with a lower occurrence of upper respiratory tract symptoms. As disentangling the effects of UVR from other relevant factors is often impossible in observational studies, concise quantitative risk estimations for the human situation cannot be given at present.SG-NO