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

The standardised G115 Panax ginseng C.A. Meyer extract: a review of its properties and usage

Ginseng (Panax ginseng C.A. Meyer, ginseng) has been the most precious and renowned tonic drug in traditional Chinese medicine. Although the original discovery of its therapeutic efficacy has been lost in antiquity, believers in ginseng as a panacea have sought, cultivated, preserved and extracted its essences for the treatment of a wide range of ailments. Many patients have used aqueous and alcoholic extracts of ginseng during convalescence, particularly where previous health problem(s) resulted in some degree of debilitation, and a corresponding deficit in mental, physical or other functional capacities. An impressive body of information has been accumulated and scientific research has documented and reviewed the useful effects of P. ginseng C.A. Meyer. The high variability in composition of the marketed products clearly affects the results of clinical studies. The availability of the standardised ginseng extract G115\uae has made it possible to generate reproducible results in animal studies and human clinical research. Active constituents found in most ginseng species include ginsenosides, polysaccharides, peptides, polyacetylenic alcohols, fatty acids and trace elements. It is generally believed that ginsenosides and their metabolites are the most important components determining the pharmacological effects of ginseng. Ginsenosides are triterpene saponins of the dammaran series. They are divided into three groups, classified according to their chemical structures: 20(S)-protopanaxadiols, 20(S)-protopanaxatriols and the RO ginsenosides. The variability in the pharmacological activities of the various ginseng species may be related to the different composition of proportions of ginsenosides. One of the most common standardised extracts, used in many studies, is G115\uae, which contains 4% ginsenosides. In view of the wide variations, both qualitative and quantitative, standardisation must control the total amount of ginsenosides. Several clinical studies have been conducted with the standardised P. ginseng extract G115\uae. Here we briefly review only double-blind, placebo-controlled trials that are judged to be of scientific relevance for the clinical profile of the product. The efficacy of G115\uae on physical performance still needs to be confirmed in Good Clinical Practice (GCP) settings. Several clinical studies with ginseng have not shown any significant effect on the enhancement of physical performance. The ability of G115\uae to increase endurance and vitality, on the other hand, has been demonstrated in a number of non-GCP studies. The efficacy of G115\uae in relieving menopausal symptoms is supported by two studies, one of GCP quality. Efficacy in improving cognitive function has been extensively reviewed. Intake of G115\uae in acute and multiple doses is associated with improvements in cognitive function. A series of studies has assessed the effects of G115\uae in various volunteer populations using a widely validated and highly sensitive computerised cognitive test system, the Cognitive Drug Research (CDR) assessment system. Several preclinical studies have indicated that G115\uae may have immunomodulatory properties. These findings have been confirmed in two clinical studies. The efficacy and safety of G115\uae for potentiating vaccination against the common cold and/or influenza syndrome in a randomised, double-blind, placebo-controlled, parallel-group, multicentre study were determined. Moreover, the effects of G115\uae in reducing the bacterial count in the bronchial system of patients undergoing an acute attack of chronic bronchitis has been investigated in an open pilot study. The safety profile of G115\uae has been well established both from clinical studies in healthy volunteers and patients and from its use for over 30 years as a marketed medicinal product in many countries worldwide. Few clinical studies on G115\uae report adverse effects. In general, the lack of reported adverse effects suggests that they are few, and those present are very minor. On the other hand, a baseline level of adverse effects should be expected and is always present, even for placebo groups in clinical trials. A total of 1075 subjects have been treated with G115\uae to date in clinical trials. Seventy-one subjects experienced minor adverse effects but no serious events were reported. The most commonly reported adverse events were headache, itching, sore throat, skin rash, dry mouth, acne and diarrhoea, with no difference between placebo and G115\uae. In all trials, no changes in safety laboratory parameters were seen

Rheological behavior of aqueous polyacrylamide solutions determined by dissipative particle dynamics and comparison to experiments

Based on molecular-dynamics simulations and experimental data, a new coarse-grained forcefield is proposed for the polyacrylamide (PAM)-water system that allows to study dynamical properties of chains at several concentrations with molecular weight up to 17000 g/mol. Non-equilibrium simulations were used to compute relative viscosities, enabling a direct comparison with experimental values. High-shear-rate measurements for low-molecular-weight PAM (10000 g/mol) were done using a microfluidic rheometer Rheosense to decrease the gap between experimental and simulated shear rates. DPD simulations reproduced qualitatively and quantitatively structural properties as well as rheological properties in the dilute regime and qualitatively in the semi-dilute regime

Comparison of the potency of different brands of serenoa repens extract on 5alpha-reductase types I and II in prostatic co-cultured epithelial and fibroblast cells

Background: Serenoa repens extract is the phytotherapeutic agent most frequently used for the treatment of the urological symptoms caused by benign prostatic hyperplasia. There are many extracts in the market and each manufacturer uses different extraction processes; for this reason, it's possible that one product is not equivalent to another. The aim of this study was to compare the activity of different extracts of Serenoa repens marketed in Italy. Methods: The following extracts were tested on 10 day co-cultured epithelial and fibroblast cells by a 5alpha-reductase activity assay: Permixon(R), Saba(R), Serpens(R), Idiprost(R), Prostamev(R), Profluss(R) and Prostil(R). In order to assess the variability in Serenoa repens products, 2 different batches for each brand were evaluated. Results and Conclusions: All extracts tested, albeit variably, are able to inhibit both isoforms of 5alpha-reductase. However, the potency of the extracts appears to be very different, as well as the potencies of 2 different batches of the same extract. This is probably due to qualitative and quantitative differences in the active ingredients. So, the product of each company must be tested to evaluate the clinical efficacy and bioactivity