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)

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

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)

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 genus Acipenser as a model for vertebrate urogenital development: the müllerian duct

The development of the mullerian duct was studied in a total of 85 specimens of Acipenser ruthenus and Acipenser baeri in the period from 7 days after hatching through 5 years of age. Normal histology on serial sections, transmission and scanning electron microscopy and bromodeoxyuridine immunohistochemistry were applied. In Acipenser, the primary set of opisthonephric nephrons possess short nephrostomial tubules with well-developed nephrostomes. Proliferating cells from the lateral side of the slightly protruding nephrostomial lips spread out over the ceolomic surface, replace here the flat mesothelium of lateral plate origin and establish the infundibular field, consisting of cuboidal or columnar cells. At about 28 days after hatching, the primordium of the mullerian infundibulum becomes visible in the form of a pocket-like invagination within the infundibular field. This invagination is found coexisting with and located laterally to the line of intact nephrostomes. The mullerian infundibulum, therefore, does not represent the homologon of a nephrostome itself, but must be regarded as a separate and secondary structure. The mullerian duct proper has its origin in cells from the bottom of the infundibular pocket. These cells grow as a tubule with a solid tip in the caudal direction, paralleling the wolffian duct, but without a contribution of cells from the latter. In Acipenser, a mullerian duct is present also in the adult male. In males as in females, the caudal extremity of the mullerian duct generally divides into two to three smaller terminals which end in the wolffian duct at different levels, but always cranial to the urogenital sinus. In most indifferent animals and in all males of this study, the tips of the mullerian terminals are closed and covered by a thin layer of wolffian epithelium. In adult females, the mullerian ducts end with open terminals. In both sexes, the adult mullerian duct is lined by a pseudostratified columnar epithelium, consisting of ciliated, non-ciliated and basal free cells

Morphogenesis of the bovine rete testis: the intratesticular rete and its connection to the seminiferous tubules

The development of the intragonadal rete testis and the establishment of the connection between seminiferous and straight testicular tubules was studied using ultrastructural and histochemical methods in 60 bovine embryos and fetuses ranging from day 39 through day 225 post conceptionem. The methodology included a modified acetylcholinesterase (AChE) reaction as a selective marker for pre-Sertoli cells and a modified microsomal aminopeptidase (MAP) reaction as a selective marker for the epithelia of rete testis and straight testicular tubules. Between 40 and 45 days, the rete testis is predominantly an extratesticular rete situated in the cranial peduncle of the gonadal fold and in broad contact with the pro/mesonephric giant corpuscle. During this period, the intragonadal rete enters the gonad proper from its craniodorsal pole and extends into the cranial fourth of the testis. Between 60 and 110 days the rete testis attains its definitive position, extending into the central longitudinal axis as far as to the caudal fourth of the testis. For the caudal expansion of the rete testis the preceding proliferation of the mediastinal stroma is an important prerequisite. In the 40 to 45-day-old embryo the area of the testicular cords may be divided into two zones. A narrow outer zone contains plate-like cords with a thick diameter, and a larger central zone is filled with a network of thinner cords. Only the thick outer cords transform into the permanent seminiferous tubules, whereas the thinner cords in the central zone are transitory structures that disappear between 45 and 110 days. One important function of these transitory cords is to establish a continuous system of basal laminae that allows a direct connection between the central ends of the growing seminiferous tubules and the peripheral extensions of the rete testis (future straight testicular tubules). The first true straight testicular tubules become visible between 85 and 110 days. Due to a strong proliferation of the tubulus rectus-cells the straight testicular tubules elongate continuously, and the border between the rete system and the seminiferous tubules is slowly shifted towards the testicular periphery. This shift is not restricted to the prenatal period, but proceeds until after birth. At the cytological level, the formation and elongation of the straight testicular tubules is effected by proliferating cells that advance along the continuous basal lamina into the area of the seminiferous tubules. The preSertoli and germ cells in this zone of invasion are separated from each other and overgrown by the tubulus rectus-cells. Exposed to the special milieu of the straight testicular tubules, preSertoli and germ cells apparently cannot survive and finally disappear