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)

Adaptive robot training for the treatment of incoordination in Multiple Sclerosis

<p>Abstract</p> <p>Background</p> <p>Cerebellar symptoms are extremely disabling and are common in Multiple Sclerosis (MS) subjects. In this feasibility study, we developed and tested a robot therapy protocol, aimed at the rehabilitation of incoordination in MS subjects.</p> <p>Methods</p> <p>Eight subjects with clinically defined MS performed planar reaching movements while grasping the handle of a robotic manipulandum, which generated forces that either reduced (error-reducing, ER) or enhanced (error-enhancing, EE) the curvature of their movements, assessed at the beginning of each session. The protocol was designed to adapt to the individual subjects' impairments, as well as to improvements between sessions (if any). Each subject went through a total of eight training sessions. To compare the effect of the two variants of the training protocol (ER and EE), we used a cross-over design consisting of two blocks of sessions (four ER and four EE; 2 sessions/week), separated by a 2-weeks rest period. The order of application of ER and EE exercises was randomized across subjects. The primary outcome measure was the modification of the Nine Hole Peg Test (NHPT) score. Other clinical scales and movement kinematics were taken as secondary outcomes.</p> <p>Results</p> <p>Most subjects revealed a preserved ability to adapt to the robot-generated forces. No significant differences were observed in EE and ER training. However over sessions, subjects exhibited an average 24% decrease in their NHPT score. The other clinical scales showed small improvements for at least some of the subjects. After training, movements became smoother, and their curvature decreased significantly over sessions.</p> <p>Conclusions</p> <p>The results point to an improved coordination over sessions and suggest a potential benefit of a short-term, customized, and adaptive robot therapy for MS subjects.</p

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

Stumbling reactions in man: significance of proprioceptive and pre-programmed mechanisms.

1. Electromyogram (e.m.g.) responses of the leg musculature and the corresponding joint movements were studied following a perturbation of the limb during walking on a treadmill, produced by a randomly timed treadmill acceleration impulse, either predictable, or unpredictable in its amplitude and rate of acceleration. 2. The rate of rise of ipsilateral gastrocnemius e.m.g. response following a perturbation was dependent on the rate of treadmill acceleration. For a given acceleration rate the amplitude of the e.m.g. response and the timing of its peak was dependent on the amplitude of the impulse and the rate of rise of the gastrocnemius response was the same for impulses of both small and large amplitude. The onset latency was shorter (65 ms) for high accelerations and longer (85 ms) for lower ones. 3. The amplitude of the ipsilateral biceps femoris response was much smaller than the gastrocnemius response but was larger following unpredictable than predictable impulses. 4. The initial gastrocnemius response was followed by a tibialis anterior activation associated with a gastrocnemius depression and sometimes with a second, weak gastrocnemius activation. The gastrocnemius depression ended within a fixed time range relative to the onset of the response. The tibialis anterior activation was most pronounced when unpredictable impulses with high acceleration but a small amplitude were induced. 5. It is concluded that generation of the first gastrocnemius response is obviously under continuous control by muscle proprioceptive information and can be best described in terms of a stretch reflex response. It is suggested that, on the evidence of the diphasic or triphasic e.m.g. pattern, a close interaction occurs between a central programme and muscle proprioceptive input in order to generate the appropriate e.m.g. pattern. 6. On the basis of earlier work (Berger, Dietz & Quintern, 1984a) and on the present results it is suggested that the e.m.g. responses may be mediated mainly by muscle proprioceptive input from group II afferents. This input is modulated and processed by spinal interneuronal circuits, closely connected with spinal locomotor centres. The mode of processing depends on various factors, such as the predictability of the nature of the impulse

P3825Long-term prognostic value of growth differentiation factor-15 in acute coronary syndrome

Abstract Introduction Biomarkers plays a critical role in diagnostic, prognostication, and decision-making in cardiovascular medicine. Growth differentiation factor-15 (GDF-15) has been reported as a potential biomarker in acute coronary syndrome (ACS). However, there is limited data on the long-term prognostic value after an ACS. Purpose To study the long-term prognostic value of GDF-15 in ACS. Methods We included patients with ACS who underwent coronary angiography. During angiography an arterial blood sample was collected. Plasma GDF-15 were measured and clinical data and long-term events were obtained. As previously reported, risk categories were defined as low risk (&lt;1200ng/L), intermediate (1200–1800ng/L) and high risk (&gt;1800ng/L). Incremental prognostic value of GDF-15 for all-cause death was assessed on top of a clinical model (GRACE score, LVEF&lt;40% and age). Results A total of 358 patients were included; 157 as a low risk, 85 as an intermediate and 116 as a high risk. The median (IQR) age was 65 (56–74) years and 27.4% were female. Of all patients, 61.5% were admitted with non-ST-elevation myocardial infarction, 24.0% with ST-elevation myocardial infarction and 14.5% with unstable angina. Higher values of GDF-15 were consistently associated with an increased prevalence of cardiovascular risk factors. During 6 years of follow-up 54 patients died. Of those patients, 7 (4.5%) had values of GDF-15 below 1200ng/L, 6 (7.1%) between 1200–1800ng/L and 41 (35.3%) above 1800ng/L. After adjustment for a multivariate Cox regression model, GDF-15 &gt;1800ng/L were independently associated with all-cause death (HR 4.5; 95% CI 1.8–11.6; p=0.002) and the composite of major adverse cardiovascular events (MACE) which were identified as all-cause death, nonfatal MI and heart failure (HR 2.5; 95% CI 1.4–4.4; p=0.001). For long-term all-cause death a significant increase of the c-statistic was seen after addition of GDF-15 to the clinical model 0.871 (95% CI 0.817–0.924; p=0.019) as well as net reclassification improvement (0.769; 95% CI 0.487–1.051; p&lt;0.001) and integrated discrimination improvement (0.117; 95% CI 0.062–0.172; p&lt;0.001). Of 18 events of heart failure, 17 occurred in patients with GDF&gt;1800ng/L. A multivariate competing risk model showed a significant association between GDF-15&gt;1800ng/L and incidence of heart failure (adjusted HR 30.8; 95% CI 4.1–231.5; p=0.001) but non-significant association were found for myocardial infarction. KM figures and all-cause death ROC curve Conclusions In the setting of ACS GDF-15 can predict long-term all-cause death, MACE and heart failure and provides incremental prognostic value beyond traditional risks factors in the long-term all-cause death. </jats:sec