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)

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

Susceptibility to stress and nature exposure: Unveiling differential susceptibility to physical environments; a randomized controlled trial.

BackgroundEmerging epidemiological evidence indicates nature exposure could be associated with greater health benefits among groups in lower versus higher socioeconomic positions. One possible mechanism underpinning this evidence is described by our framework: (susceptibility) adults in low socioeconomic positions face higher exposure to persistent psychosocial stressors in early life, inducing a pro-inflammatory phenotype as a lifelong susceptibility to stress; (differential susceptibility) susceptible adults are more sensitive to the health risks of adverse (stress-promoting) environments, but also to the health benefits of protective (stress-buffering) environments.ObjectiveExperimental investigation of a pro-inflammatory phenotype as a mechanism facilitating greater stress recovery from nature exposure.MethodsWe determined differences in stress recovery (via heart rate variability) caused by exposure to a nature or office virtual reality environment (10 min) after an acute stressor among 64 healthy college-age males with varying levels of susceptibility (socioeconomic status, early life stress, and a pro-inflammatory state [inflammatory reactivity and glucocorticoid resistance to an in vitro bacterial challenge]).ResultsFindings for inflammatory reactivity and glucocorticoid resistance were modest but consistently trended towards better recovery in the nature condition. Differences in recovery were not observed for socioeconomic status or early life stress.DiscussionAmong healthy college-age males, we observed expected trends according to their differential susceptibility when assessed as inflammatory reactivity and glucocorticoid resistance, suggesting these biological correlates of susceptibility could be more proximal indicators than self-reported assessments of socioeconomic status and early life stress. If future research in more diverse populations aligns with these trends, this could support an alternative conceptualization of susceptibility as increased environmental sensitivity, reflecting heightened responses to adverse, but also protective environments. With this knowledge, future investigators could examine how individual differences in environmental sensitivity could provide an opportunity for those who are the most susceptible to experience the greatest health benefits from nature exposure

Virtual reality environments.

Equirectangular depictions of the 360-degree 8k stationary recordings (Insta360 Pro™, Insta360.Inc, Shenzhen, Hong Kong) delivered in virtual reality using a commercial headset (VIVE Pro™, HTC Corporation, Taoyuan, Taiwan) after participants experienced an acute stressor. The virtual greenspace environment (nature) was recorded at a public park within the same county as the university where the exposure experiment was conducted. The virtual indoor environment (office) was recorded at the same university office used for the experiment. Participants were seated in a chair for the duration of the exposure (10 min).</p

Flow diagram of exposure experiment.

Stress recovery was assessed using heart rate variability to index changes in autonomic activation (sympathetic and parasympathetic) from baseline to the recovery period. Susceptibility indicators (socioeconomic status, early life stress, inflammatory reactivity, and glucocorticoid resistance) were assessed at various time points. Socioeconomic status (MacArthur Scale of Subjective Social Status) and early life stress (Adverse Childhood Experience Questionnaire) were measured during an initial visit to the laboratory within three days of the exposure experiment. Inflammatory reactivity and glucocorticoid resistance (in vitro bacterial challenge) were assessed using serum collected before the start of the exposure experiment.</p

Forest plots of standardized effects (Binary interaction terms).

Forest plots visualizing interaction terms (standardized coefficients and confidence intervals [95%]) across all multiple regression models. Within these plots, all models were specified so that among participants with high versus low susceptibility (binary; median-value), positive interaction terms indicate greater stress recovery (increased parasympathetic and reduced sympathetic activation) in the nature versus office condition while negative terms indicate greater stress recovery in the office versus nature condition. Interaction terms at zero indicate no differences in the association between susceptibility and stress recovery (autonomic activation) by condition group. * p (TIF)</p

Interaction plots: Maximum information.

Interaction plots visualizing significant associations (slopes) between susceptibility and stress recovery (autonomic activation) by condition group (nature [solid black line] versus office [dashed gray line]). Y-axes present sympathetic or parasympathetic activation using fitted values (unstandardized) from the corresponding regression model (baseline adjusted metric of autonomic activity [log] during the recovery period [40 min]). X-axes present susceptibility indicators using log-values. P-values denote the simple slope for the nature (black) or office (gray) condition; error bands represent the standard error for each slope. Points denote participants in the nature (black triangle) or office (gray circle) condition. Type III effects represent the interaction term. (TIF)</p

Participant characteristics.

BackgroundEmerging epidemiological evidence indicates nature exposure could be associated with greater health benefits among groups in lower versus higher socioeconomic positions. One possible mechanism underpinning this evidence is described by our framework: (susceptibility) adults in low socioeconomic positions face higher exposure to persistent psychosocial stressors in early life, inducing a pro-inflammatory phenotype as a lifelong susceptibility to stress; (differential susceptibility) susceptible adults are more sensitive to the health risks of adverse (stress-promoting) environments, but also to the health benefits of protective (stress-buffering) environments.ObjectiveExperimental investigation of a pro-inflammatory phenotype as a mechanism facilitating greater stress recovery from nature exposure.MethodsWe determined differences in stress recovery (via heart rate variability) caused by exposure to a nature or office virtual reality environment (10 min) after an acute stressor among 64 healthy college-age males with varying levels of susceptibility (socioeconomic status, early life stress, and a pro-inflammatory state [inflammatory reactivity and glucocorticoid resistance to an in vitro bacterial challenge]).ResultsFindings for inflammatory reactivity and glucocorticoid resistance were modest but consistently trended towards better recovery in the nature condition. Differences in recovery were not observed for socioeconomic status or early life stress.DiscussionAmong healthy college-age males, we observed expected trends according to their differential susceptibility when assessed as inflammatory reactivity and glucocorticoid resistance, suggesting these biological correlates of susceptibility could be more proximal indicators than self-reported assessments of socioeconomic status and early life stress. If future research in more diverse populations aligns with these trends, this could support an alternative conceptualization of susceptibility as increased environmental sensitivity, reflecting heightened responses to adverse, but also protective environments. With this knowledge, future investigators could examine how individual differences in environmental sensitivity could provide an opportunity for those who are the most susceptible to experience the greatest health benefits from nature exposure.</div

Nature exposure and stress recovery (Autonomic activation).

Mean and error plots visualizing group differences in sympathetic (LF/HF, SNS, HR↑) or parasympathetic (RMSSD, PNS, HR↓) activation during the exposure (left) or recovery (right) periods. Y-axis present mean differences between the nature versus office group obtained from the pairwise contrasts (mixed effect models with interaction terms). Points and confidence intervals (95% error bars) represent the nature condition compared to the office condition (dashed black line; y-intercept at zero). (TIF)</p