Clinical Outcomes in Older Patients with Atrial Fibrillation: Insights from the GARFIELD-AF Registry.

BACKGROUND: Oral anticoagulants (OAC) are underutilized in older patients with atrial fibrillation, despite proven clinical benefits. Our objective was to investigate baseline characteristics, treatment patterns, and impact of anticoagulation upon clinical outcomes with respect to age. METHODS: Adults with newly diagnosed atrial fibrillation were recruited into the prospective observational registry, GARFIELD-AF, and followed up for 24 months. Adjusted hazard ratios (HR) were obtained via Cox proportional-hazards models with applied weights, to quantify the association of age with clinical outcomes. Comparative effectiveness of OAC vs No OAC and non-vitamin K oral anticoagulants (NOAC) vs vitamin K antagonists (VKA) were assessed using a propensity score with an overlap weighting scheme. RESULTS: Of 52,018 patients, 32.6% were 65-74 years of age, 29.3% were 75-84 years, and 7.9% were ≥85 years. OAC treatment was associated with a numerical reduction in all-cause mortality among those aged 65-74 years (HR; 95% confidence interval) (0.86; 0.69-1.06) and aged 75-84 years (0.89; 0.75-1.05) and a significant reduction in patients ≥85 years (0.77; 0.63-0.95) vs no OAC. Similarly, OACs were associated with a decrease in stroke: 65-74 (0.51; 0.35-0.76) and ≥85 years (0.58; 0.34-0.99) and a numerical decrease in 75-84 years (0.84; 0.59-1.18). No increase in major bleeding was observed in patients aged ≥85 treated with OACs. Compared with VKA, NOACs were associated with a significant reduction in all-cause mortality in patients aged <65 and 65-74, with numerical reductions in those aged 75-84 and ≥85 years. CONCLUSIONS: Older patients using OACs saw lower all-cause mortality and stroke risk; NOACs had less mortality and major bleeding compared with VKAs.

Enoxaparin for symptomatic COVID-19 managed in the ambulatory setting: An individual patient level analysis of the OVID and ETHIC trials.

BACKGROUND: Antithrombotic treatment may improve the disease course in non-critically ill, symptomatic COVID-19 outpatients. METHODS: We performed an individual patient-level analysis of the OVID and ETHIC randomized controlled trials, which compared enoxaparin thromboprophylaxis for either 14 (OVID) or 21 days (ETHIC) vs. no thromboprophylaxis for outpatients with symptomatic COVID-19 and at least one additional risk factor. The primary efficacy outcome included all-cause hospitalization and all-cause death within 30 days from randomization. Both studies were prematurely stopped for futility. Secondary efficacy outcomes were major symptomatic venous thromboembolic events, arterial cardiovascular events, or their composite occurring within 30 days from randomization. The same outcomes were assessed over a 90-day follow-up. The primary safety outcome was major bleeding (ISTH criteria). RESULTS: A total of 691 patients were randomized: 339 to receive enoxaparin and 352 to the control group. Over 30-day follow-up, the primary efficacy outcome occurred in 6.0 % of patients in the enoxaparin group vs. 5.8 % of controls for a risk ratio (RR) of 1.05 (95%CI 0.57-1.92). The incidence of major symptomatic venous thromboembolic events and arterial cardiovascular events was 0.9 % vs. 1.8 %, respectively (RR 0.52; 95%CI 0.13-2.06). Most cardiovascular thromboembolic events were represented by symptomatic venous thromboembolic events, occurring in 0.6 % vs. 1.5 % of patients, respectively. A similar distribution of outcomes between the treatment groups was observed over 90 days. No major bleeding occurred in the enoxaparin group vs. one (0.3 %) in the control group. CONCLUSIONS: We found no evidence for the clinical benefit of early administration of enoxaparin thromboprophylaxis in outpatients with symptomatic COVID-19. These results should be interpreted taking into consideration the relatively low occurrence of events.

Determinants and clinical outcomes of patients who refused anticoagulation: findings from the global GARFIELD-AF registry.

OBJECTIVE: There is a substantial incidence of stroke in patients with atrial fibrillation (AF) not receiving anticoagulation. The reasons for not receiving anticoagulation are generally attributed to clinician's choice, however, a proportion of AF patients refuse anticoagulation. The aim of our study was to investigate factors associated with patient refusal of anticoagulation and the clinical outcomes in these patients. METHODS: Our study population comprised patients in the Global Anticoagulant Registry in the FIELD (GARFIELD-AF) registry with CHA2DS2-VASc≥2. A logistic regression was developed with predictors of patient anticoagulation refusal identified by least absolute shrinkage and selection operator methodology. Patient demographics, medical and cardiovascular history, lifestyle factors, vital signs (body mass index, pulse, systolic and diastolic blood pressure), type of AF and care setting at diagnosis were considered as potential predictors. We also investigated 2-year outcomes of non-haemorrhagic stroke/systemic embolism (SE), major bleeding and all-cause mortality in patients who refused versus patients who received and patients who did not receive anticoagulation for other reasons. RESULTS: Out of 43 154 AF patients, who were at high risk of stroke, 13 283 (30.8%) did not receive anticoagulation at baseline. The reason for not receiving anticoagulation was unavailable for 38.7% (5146/13 283); of the patients with a known reason for not receiving anticoagulation, 12.5% (1014/8137) refused anticoagulation. Diagnosis in primary care/general practitioner, Asian ethnicity and presence of vascular disease were strongly associated with a higher risk of patient refusal of anticoagulation. Patient refusal of anticoagulation was associated with a higher risk of non-haemorrhagic stroke/SE (adjusted HR (aHR) 1.16 (95% CI 0.77 to 1.76)) but lower all-cause mortality (aHR 0.59 (95% CI 0.43 to 0.80)) compared with patients who received anticoagulation. The GARFIELD-AF mortality score corroborated this result. CONCLUSION: The data suggest patient refusal of anticoagulation is a missed opportunity to prevent AF-related stroke. Further research is required to understand the patient profile and mortality outcome of patients who refuse anticoagulation.

Thromboprophylactic low-molecular-weight heparin versus standard of care in unvaccinated, at-risk outpatients with COVID-19 (ETHIC): an open-label, multicentre, randomised, controlled, phase 3b trial.

BACKGROUND: COVID-19 is associated with inflammation and an increased risk of thromboembolic complications. Prophylactic doses of low-molecular-weight heparin have been used in hospitalised and non-critically ill patients with COVID-19. We aimed to evaluate the efficacy and safety of prophylactic low-molecular-weight heparin (enoxaparin) versus standard of care (no enoxaparin) in at-risk outpatients with COVID-19. METHODS: This open-label, multicentre, randomised, controlled, phase 3b trial (ETHIC) was done at 15 centres in six countries (Belgium, Brazil, India, South Africa, Spain, and the UK). We consecutively enrolled participants aged at least 30 years who had not received a COVID-19 vaccine and had symptomatic, confirmed COVID-19 in the outpatient setting plus at least one risk factor for severe disease. Within 9 days of symptom onset and by use of a web-based random block design (block size either 2 or 4), eligible participants were randomly assigned (1:1) to receive either subcutaneous enoxaparin for 21 days (40 mg once daily if they weighed <100 kg and 40 mg twice daily if they weighed ≥100 kg) or standard of care (without enoxaparin). The primary efficacy endpoint was the composite of all-cause hospitalisation and all-cause mortality at 21 days after randomisation and, in our main analysis, was analysed in the intention-to-treat population, which comprised all patients who were randomly assigned. Safety was also analysed in the intention-to-treat population for our main analysis. This trial is registered with ClinicalTrials.gov, NCT04492254, and is complete. FINDINGS: Following the advice of the Data and Safety Monitoring Board, this study was terminated early due to slow enrolment and a lower-than-expected event rate. Between Oct 27, 2020, and Nov 8, 2021, 230 patients with COVID-19 were assessed for eligibility, of whom 219 were enrolled and randomly assigned to receive standard of care (n=114) or enoxaparin (n=105). 96 (44%) patients were women, 122 (56%) were men, and one patient had missing sex data. 141 (65%) of 218 participants with data on race and ethnicity were White, 60 (28%) were Asian, and 16 (7%) were Black, mixed race, or Arab or Middle Eastern. Median follow-up in both groups was 21 days (IQR 21-21). There was no difference in the composite of all-cause mortality and hospitalisation at 21 days between the enoxaparin group (12 [11%] of 105 patients) and the standard-of-care group (12 [11%] of 114 patients; unadjusted hazard ratio 1·09 [95% CI 0·49-2·43]; log-rank p=0·83). At 21 days, two (2%) of 105 patients in the enoxaparin group (one minor bleed and one bleed of unknown severity) and one (1%) of 114 patients in the standard-of-care group (major abnormal uterine bleeding) had a bleeding event. 22 (21%) patients in the enoxaparin group and 13 (11%) patients in the standard-of-care group had adverse events. The most common adverse event in both groups was COVID-19-related pneumonia (six [6%] patients in the enoxaparin group and five [4%] patients in the standard-of-care group). One patient in the enoxaparin group died and their cause of death was unknown. INTERPRETATION: The ETHIC trial results suggest that prophylaxis with low-molecular-weight heparin had no benefit for at-risk outpatients with COVID-19. Although the trial was terminated early, our data, combined with data from similar studies, provide further insights to inform international guidelines and influence clinical practice. FUNDING: The Thrombosis Research Institute and Sanofi UK.

Risks associated with discontinuation of oral anticoagulation in newly diagnosed patients with atrial fibrillation: Results from the GARFIELD-AF Registry.

BACKGROUND: Oral anticoagulation (OAC) in atrial fibrillation (AF) reduces the risk of stroke/systemic embolism (SE). The impact of OAC discontinuation is less well documented. OBJECTIVE: Investigate outcomes of patients prospectively enrolled in the Global Anticoagulant Registry in the Field-Atrial Fibrillation study who discontinued OAC. METHODS: Oral anticoagulation discontinuation was defined as cessation of treatment for ≥7 consecutive days. Adjusted outcome risks were assessed in 23 882 patients with 511 days of median follow-up after discontinuation. RESULTS: Patients who discontinued (n = 3114, 13.0%) had a higher risk (hazard ratio [95% CI]) of all-cause death (1.62 [1.25-2.09]), stroke/systemic embolism (SE) (2.21 [1.42-3.44]) and myocardial infarction (MI) (1.85 [1.09-3.13]) than patients who did not, whether OAC was restarted or not. This higher risk of outcomes after discontinuation was similar for patients treated with vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) (p for interactions range = 0.145-0.778). Bleeding history (1.43 [1.14-1.80]), paroxysmal vs. persistent AF (1.15 [1.02-1.29]), emergency room care setting vs. office (1.37 [1.18-1.59]), major, clinically relevant nonmajor, and minor bleeding (10.02 [7.19-13.98], 2.70 [2.24-3.25] and 1.90 [1.61-2.23]), stroke/SE (4.09 [2.55-6.56]), MI (2.74 [1.69-4.43]), and left atrial appendage procedures (4.99 [1.82-13.70]) were predictors of discontinuation. Age (0.84 [0.81-0.88], per 10-year increase), history of stroke/transient ischemic attack (0.81 [0.71-0.93]), diabetes (0.88 [0.80-0.97]), weeks from AF onset to treatment (0.96 [0.93-0.99] per week), and permanent vs. persistent AF (0.73 [0.63-0.86]) were predictors of lower discontinuation rates. CONCLUSIONS: In GARFIELD-AF, the rate of discontinuation was 13.0%. Discontinuation for ≥7 consecutive days was associated with significantly higher all-cause mortality, stroke/SE, and MI risk. Caution should be exerted when considering any OAC discontinuation beyond 7 days.

Bleeding and related mortality with NOACs and VKAs in newly diagnosed atrial fibrillation: results from the GARFIELD-AF registry.

In atrial fibrillation (AF), lower risks of death and bleeding with non-vitamin-K oral anticoagulants (NOACs) were reported in meta-analyses of controlled trials, but whether these findings hold true in real-world practice remains uncertain. Risks of bleeding and death were assessed in 52 032 patients with newly diagnosed AF enrolled in GARFIELD-AF (Global Anticoagulant Registry in the FIELD-Atrial Fibrillation), a worldwide prospective registry. Baseline treatment was vitamin K antagonists (VKAs) with or without antiplatelet (AP) agents (VKA ± AP) (20 151; 39.3%), NOACs ± AP agents (14 103; 27.5%), AP agents only (10 748; 21.0%), or no antithrombotics (6219; 12.1%). One-year follow-up event rates (95% confidence interval [CI]) of minor, clinically relevant nonmajor (CRNM), and major bleedings were 2.29 (2.16-2.43), 1.10 (1.01-1.20), and 1.31 (1.21-1.41) per 100 patient-years, respectively. Bleeding risk was lower with NOACs than VKAs for any bleeding (hazard ratio (HR) [95% CI]), 0.85 [0.73-0.98]) or major bleeding (0.79 [0.60-1.04]). Compared with no bleeding, the risk of death was higher with minor bleeding (adjusted HR [aHR], 1.53 [1.07-2.19]), CRNM bleeding (aHR, 2.59 [1.80-3.73]), and major bleeding (aHR, 8.24 [6.76-10.04]). The all-cause mortality rate was lower with NOACs than with VKAs (aHR, 0.73 [0.62-0.85]). Forty-five percent (114) of all deaths occurred within 30 days, and 40% of these were from intracranial/intraspinal hemorrhage (ICH). The rates of any bleeding and all-cause death were lower with NOACs than with VKAs. Major bleeding was associated with the highest risk of death. CRNM bleeding and minor bleeding were associated with a higher risk of death compared to no bleeding. Death within 30 days after a major bleed was most frequently related to ICH. This trial was registered at www.clinicaltrials.gov as #NCT01090362.

Characteristics of patients with atrial fibrillation prescribed edoxaban in Belgium and The Netherlands: insights from the ETNA-AF-Europe study.

BACKGROUND: Studies on the use of non-vitamin K antagonist oral anticoagulants in unselected patients with atrial fibrillation (AF) show that clinical characteristics and dosing practices differ per region, but lack data on edoxaban. METHODS: With data from Edoxaban Treatment in routiNe clinical prActice for patients with AF in Europe (ETNA-AF-Europe), a large prospective observational study, we compared clinical characteristics (including the dose reduction criteria for edoxaban: creatinine clearance 15-50 mL/min, weight ≤60 kg, and/or use of strong p-glycoprotein inhibitors) of patients from Belgium and the Netherlands (BeNe) with those from other European countries (OEC). RESULTS: Of all 13,639 patients in ETNA-AF-Europe, 2579 were from BeNe. BeNe patients were younger than OEC patients (mean age: 72.3 vs 73.9 years), and had lower CHA2DS2-VASc (mean: 2.8 vs 3.2) and HAS-BLED scores (mean: 2.4 vs 2.6). Patients from BeNe less often had hypertension (61.6% vs 80.4%), and/or diabetes mellitus (17.3% vs 23.1%) than patients from OEC. Moreover, relatively fewer patients in BeNe were prescribed the reduced dose of 30 mg edoxaban (14.8%) than in OEC (25.4%). Overall, edoxaban was dosed according to label in 83.1% of patients. Yet, 30 mg edoxaban was prescribed in the absence of any dose reduction criteria in 36.9% of 30 mg users (5.5% of all patients) in BeNe compared with 35.5% (9.0% of all patients) in OEC. CONCLUSION: There were several notable differences between BeNe and OEC regarding clinical characteristics and dosing practices in patients prescribed edoxaban, which are relevant for the local implementation of dose evaluation and optimisation. TRIAL REGISTRATION: NCT02944019; Date of registration: October 24, 2016.

GARFIELD-AF: a worldwide prospective registry of patients with atrial fibrillation at risk of stroke.

The Global Anticoagulant Registry in the Field-Atrial Fibrillation (GARFIELD-AF) examined real-world practice in a total of 57,149 (5069 retrospective, 52,080 prospective) patients with newly diagnosed AF at risk of stroke/systemic embolism, enrolled at over 1000 centers in 35 countries. It aimed to capture data on AF burden, patients' clinical profile, patterns of clinical practice and antithrombotic management, focusing on stroke/systemic embolism prevention, uptake of new oral anticoagulants, impact on death and bleeding. GARFIELD-AF set new standards for quality of data collection and analysis. A total of 36 peer-reviewed articles were already published and 73 abstracts presented at international congresses, covering treatment strategies, geographical variations in baseline risk and therapies, adverse outcomes and common comorbidities such as heart failure. A risk prediction tool as well as innovative observational studies and artificial intelligence methodologies are currently being developed by GARFIELD-AF researchers. Clinical Trial Registration: NCT01090362 (ClinicalTrials.gov).

Mortality in Patients With Atrial Fibrillation Receiving Nonrecommended Doses of Direct Oral Anticoagulants.

BACKGROUND: The recommended doses for direct oral anticoagulants (DOACs) to prevent stroke and systemic embolism (SE) in patients with atrial fibrillation (AF) are described in specific regulatory authority approvals. OBJECTIVES: The impact of DOAC dosing, according to the recommended guidance on all-cause mortality, stroke/SE, and major bleeding, was assessed at 2-year follow-up in patients with newly diagnosed AF. METHODS: Of a total of 34,926 patients enrolled (2013 to 2016) in the prospective GARFIELD-AF (Global Anticoagulant Registry in the FIELD-AF), 10,426 patients received a DOAC. RESULTS: The majority of patients (72.9%) received recommended dosing, 23.2% were underdosed, and 3.8% were overdosed. Nonrecommended dosing (underdosage and overdosage combined) compared with recommended dosing was associated with a higher risk of all-cause mortality (hazard ratio [HR]: 1.24; 95% confidence interval [CI]: 1.04 to 1.48); HR: 1.25 (95% CI: 1.04 to 1.50) for underdosing, and HR: 1.19 (95% CI: 0.83 to 1.71) for overdosing. The excess deaths were cardiovascular including heart failure and myocardial infarction. The risks of stroke/SE and major bleeding were not significantly different irrespective of the level of dosing, although underdosed patients had a significantly lower risk of bleeding. A nonsignificant trend to higher risks of stroke/SE (HR: 1.51; 95% CI: 0.79 to 2.91) and major bleeding (HR: 1.29; 95% CI: 0.59 to 2.78) was observed in patients with overdosing. CONCLUSIONS: In GARFIELD-AF, most patients received the recommended DOAC doses according to country-specific guidelines. Prescription of nonrecommended doses was associated with an increased risk of death, mostly cardiovascular death, compared with patients on recommended doses, after adjusting for baseline factors. (Global Anticoagulant Registry in the Field-AF [GARFIELD-AF]; NCT01090362).

Impact of different anticoagulation management strategies on outcomes in atrial fibrillation: Dutch and Belgian results from the GARFIELD-AF registry.

BACKGROUND: The uptake rate of non-vitamin K oral anticoagulants (NOAC) for the treatment of non-valvular atrial fibrillation (AF) was far lower in the Netherlands (NL) compared to Belgium (BE). Also, patients on VKA in NL were treated with a higher target international normalized ratio (INR) range of 2.5 to 3.5. OBJECTIVES: To explore the effect of these differences on thromboembolism (TE) and bleeding. METHODS: Data from the GARFIELD-AF registry was used. Patients with new-onset AF and ≥1 investigator-determined risk factor for stroke were included between 2010 and 2016. Event rates from 2 years of follow-up were used. RESULTS: In NL and BE, 1186 and 1705 patients were included, respectively. Female sex (42.3% vs 42.2%), mean age (70.7 vs 71.3 years), CHA2 DS2 -VASc (3.1 vs 3.1), and HAS-BLED score (1.4 vs 1.5) were comparable between NL and BE. At diagnosis in NL vs BE, 72.1% vs 14.6% received vitamin K antagonists (VKA) and 17.8% vs 65.5% NOACs, varying greatly across cohorts. Mean INR was 2.9 (±1.0) and 2.4 (±1.0) in NL and BE, respectively. Event rates per 100 patient-years in NL and BE, respectively, of all-cause mortality (3.38 vs 3.90; hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.65-1.15), ischemic stroke/TE (0.82 vs 0.72; HR 1.14, 95% CI 0.62-2.11), and major bleeding (2.06 vs 1.54; HR 1.33, 95% CI 0.89-1.99) did not differ significantly. CONCLUSIONS: In GARFIELD-AF, despite similar characteristics, patients on anticoagulants were treated differently in NL and BE. Although the rate of major bleeding was 33% higher in NL, variations in bleeding, mortality, and TE rates were not statistically significant.

Use of the Actiwatch-Mini® in dog safety studies as an early indicator for drug-induced behavioural changes.

INTRODUCTION: Clinical observations are routinely used to address drug-induced behavioural changes in dogs. To deal with the limitations of this methodology, we evaluated Actiwatch-Mini® as a tool to monitor continuously locomotor activity in dogs and to provide objective parameters that could be linked to behavioural changes after compound administration. METHODS: Eight Beagles were equipped with Actiwatch-Mini®. As a reference drug, a PDE2-inhibitor was administered daily for six days at doses known to cause minor or severe behavioural changes. RESULTS: While traditional observation showed no behavioural changes - except sedation - dogs receiving 0.5 mg/kg/day, showed significant increases in % immobile time (+15.8%) and mean length of immobile phases (+1.2 min) but no change in number of immobile phases (+2.2). At 1 mg/kg/day, light to severe changes in behaviour were present. Actiwatch-Mini® recorded an increase in mean length of immobile phases (+1.9 min) and a decrease in mean number of immobile phases (-7.4) in the first four hours after each dosing while total % immobile time was not significantly increased (+4.9%). DISCUSSION: Actiwatch-Mini® was able to detect changes in immobility parameters in dogs dosed with a PDE2-inhibitor while no or only minor behavioural changes were observed. The system can be used for continuously monitoring the activity of dogs, to provide objective scores for evaluation of activity. It provides an inexpensive and low labour-intensive method for detecting changes in activity and possible early indications of drug-induced behavioural changes.

Echocardiographic and hemodynamic indices of myocardial contractility simultaneously evaluated in telemetered beagle dogs: A HESI-sponsored cross-company evaluation.

INTRODUCTION: Alterations in cardiac contractility can have significant clinical implications, highlighting the need for early detection of potential liabilities. Pre-clinical methods to assess contractility are typically invasive and their translation to human measures of cardiac function are not well defined. Clinically, cardiac function is most often measured non-invasively using echocardiography. The objective of these studies was to introduce echocardiography into standard large animal cardiovascular safety pharmacology studies and determine the feasibility of this combination. METHODS: A consortia of laboratories combined their data sets for evaluation. At each site, telemetered beagle dogs, in a 4 × 4 Latin square crossover study design (n = 4), were administered either pimobendan (positive inotrope) or atenolol (negative inotrope) orally at clinically relevant dose levels. Standard telemetry parameters were collected (heart rate, mean arterial blood pressure, etc.) continuously over 24 h, as well as derived contractility endpoints: QA interval and LV +dP/dtmax. At Tmax, echocardiography was performed in conscious dogs with minimal restraint to collect contractility parameters: ejection fraction (EF) and fractional shortening (FS). RESULTS: Correlations between telemetry and echo contractility endpoints showed that, in general, a change in LV +dP/dtmax of 1000 mmHg/s translates to a 5.2% change in EF and a 4.2% change in FS. Poor correlations were shown between QA interval derived simultaneously, to both EF and FS. DISCUSSION: Comparing data from telemetry-only groups to those that included echocardiography collections showed no effect in the ability to interpret test article-related effects, providing the foundation for the inclusion of echocardiography without compromising standard telemetry data quality.

Predictors of NOAC versus VKA use for stroke prevention in patients with newly diagnosed atrial fibrillation: Results from GARFIELD-AF.

INTRODUCTION: A principal aim of the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) was to document changes in treatment practice for patients with newly diagnosed atrial fibrillation during an era when non-vitamin K antagonist oral anticoagulants (NOACs) were becoming more widely adopted. In these analyses, the key factors which determined the choice between NOACs and vitamin K antagonists (VKAs) are explored. METHODS: Logistic least absolute shrinkage and selection operator regression determined predictors of NOAC and VKA use. Data were collected from 24,137 patients who were initiated on AC ±â€¯antiplatelet (AP) therapy (NOAC [51.4%] or VKA [48.6%]) between April 2013 and August 2016. RESULTS: The most significant predictors of AC therapy were country, enrolment year, care setting at diagnosis, AF type, concomitant AP, and kidney disease. Patients enrolled in emergency care or in the outpatient setting were more likely to receive a NOAC than those enrolled in hospital (OR 1.16 [95% CI: 1.04-1.30], OR: 1.15 [95% CI: 1.05-1.25], respectively). NOAC prescribing seemed to be favored in lower-risk groups, namely, patients with paroxysmal AF, normotensive patients, and those with moderate alcohol consumption, but also the elderly and patients with acute coronary syndrome. By contrast, VKAs were preferentially used in patients with permanent AF, moderate to severe kidney disease, heart failure, vascular disease, and diabetes and with concomitant AP. CONCLUSION: GARFIELD-AF data highlight marked heterogeneity in stroke prevention strategies globally. Physicians are adopting an individualized approach to stroke prevention where NOACs are favored in patients with a lower stroke risk but also in the elderly and patients with acute coronary syndrome.

Treatment patterns in anticoagulant therapy in patients with newly diagnosed atrial fibrillation in Belgium: results from the GARFIELD-AF registry.

Background: AF, anticoagulation, NOACs, changing patterns of prescription. Methods: We describe baseline data and treatment patterns of patients recruited in Belgium in the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF). Recruitment began when novel oral anticoagulants (NOACs) were introduced and provides a unique picture of changing treatment patterns over time. 1713 patients with a new (≤6 weeks duration) diagnosis of non-valvular atrial fibrillation (NVAF) and at least one investigator-defined stroke risk factor were recruited between May 2012 and August 2016, and will be prospectively followed for at least 2 years. Results: Overall, anticoagulant use in Belgium was higher than in the rest of Europe: 80.1% of patients received an anticoagulant ± antiplatelet (AP) therapy (14.5% on vitamin K antagonists; 65.6% on NOAC), 10.7% AP therapy and 9.3% no antithrombotic therapy. Over time, we observed an increase in anticoagulant use and a decrease in AP use for stroke prevention. NOAC use in Belgium was the highest of Europe at the study start, with many countries catching up later. In high stroke risk patients (CHA2DS2-VASc ≥2), anticoagulants were used in 84.3%, leaving 15.7% unprotected. In low risk patients (CHA2DS2-VASc 0-1) anticoagulants were overused (58.7%). Factor Xa inhibitors were used more frequently than direct thrombin inhibitors. Conclusion: Guideline adherence on stroke prevention was higher in Belgium than in the rest of Europe, and increased over time. NOAC use in Belgium was the highest of Europe at the study start, with many countries catching up later. Possible reasons are discussed. Clinical Trial Registration: http://www.clinicaltrials.gov . Unique identifier: NCT01090362.

Characteristics of patients with atrial fibrillation prescribed antiplatelet monotherapy compared with those on anticoagulants: insights from the GARFIELD-AF registry.

Aims: Current atrial fibrillation (AF) guidelines discourage antiplatelet (AP) monotherapy as alternative to anticoagulants (ACs). Why AP only is still used is largely unknown. Methods and results: Factors associated with AP monotherapy prescription were analysed in GARFIELD-AF, a registry of patients with newly diagnosed (≤6 weeks) AF and ≥1 investigator-determined stroke risk factor. We analysed 51 270 patients from 35 countries enrolled into five sequential cohorts between 2010 and 2016. Overall, 20.7% of patients received AP monotherapy, 52.1% AC monotherapy, and 14.1% AP + AC. Most AP monotherapy (82.5%) and AC monotherapy (86.8%) patients were CHA2DS2-VASc ≥2. Compared with patients on AC monotherapy, AP monotherapy patients were frequently Chinese (vs. Caucasian, odds ratio 2.73) and more likely to have persistent AF (1.32), history of coronary artery disease (2.41) or other vascular disease (1.67), bleeding (2.11), or dementia (1.81). The odds for AP monotherapy increased with 5 years of age increments for patients ≥75 years (1.24) but decreased with age increments for patients 55-75 years (0.86). Antiplatelet monotherapy patients were less likely to have paroxysmal (0.67) or permanent AF (0.57), history of embolism (0.56), or alcohol use (0.90). With each cohort, AP monotherapy declined (P<0.0001), especially non-indicated use. AP + AC and no antithrombotic therapy were unchanged. However, even in 2015 and 2016, about 50% of AP-treated patients had no indication except AF (71% were CHA2DS2-VASc ≥2). Conclusion: Prescribing AP monotherapy in newly diagnosed AF has declined, but even nowadays a substantial proportion of AP-treated patients with AF have no indication for AP. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362.

Evolving antithrombotic treatment patterns for patients with newly diagnosed atrial fibrillation.

OBJECTIVE: We studied evolving antithrombotic therapy patterns in patients with newly diagnosed non-valvular atrial fibrillation (AF) and ≥1 additional stroke risk factor between 2010 and 2015. METHODS: 39 670 patients were prospectively enrolled in four sequential cohorts in the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF): cohort C1 (2010-2011), n=5500; C2 (2011-2013), n=11 662; C3 (2013-2014), n=11 462; C4 (2014-2015), n=11 046. Baseline characteristics and antithrombotic therapy initiated at diagnosis were analysed by cohort. RESULTS: Baseline characteristics were similar across cohorts. Median CHA2DS2-VASc (cardiac failure, hypertension, age ≥75 (doubled), diabetes, stroke (doubled)-vascular disease, age 65-74 and sex category (female)) score was 3 in all four cohorts. From C1 to C4, the proportion of patients on anticoagulant (AC) therapy increased by almost 15% (C1 57.4%; C4 71.1%). Use of vitamin K antagonist (VKA)±antiplatelet (AP) (C1 53.2%; C4 34.0%) and AP monotherapy (C1 30.2%; C4 16.6%) declined, while use of non-VKA oral ACs (NOACs)±AP increased (C1 4.2%; C4 37.0%). Most CHA2DS2-VASc ≥2 patients received AC, and this proportion increased over time, largely driven by NOAC prescribing. NOACs were more frequently prescribed than VKAs in men, the elderly, patients of Asian ethnicity, those with dementia, or those using non-steroidal anti-inflammatory drugs, and current smokers. VKA use was more common in patients with cardiac, vascular, or renal comorbidities. CONCLUSIONS: Since NOACs were introduced, there has been an increase in newly diagnosed patients with AF at risk of stroke receiving guideline-recommended therapy, predominantly driven by increased use of NOACs and reduced use of VKA±AP or AP alone. TRIAL REGISTRATION NUMBER: NCT01090362; Pre-results.

Models for zero-inflated, correlated count data with extra heterogeneity: when is it too complex?

Statistical analysis of count data typically starts with a Poisson regression. However, in many real-life applications, it is observed that the variation in the counts is larger than the mean, and one needs to deal with the problem of overdispersion in the counts. Several factors may contribute to overdispersion: (1) unobserved heterogeneity due to missing covariates, (2) correlation between observations (such as in longitudinal studies), and (3) the occurrence of many zeros (more than expected from the Poisson distribution). In this paper, we discuss a model that allows one to explicitly take each of these factors into consideration. The aim of this paper is twofold: (1) investigate whether we can identify the cause of overdispersion via model selection, and (2) investigate the impact of a misspecification of the model on the power of a covariate. The paper is motivated by a study of the occurrence of drug-induced arrhythmia in beagle dogs based on electrocardiogram recordings, with the objective to evaluate the effect of potential drugs on the heartbeat irregularities. Copyright © 2016 John Wiley & Sons, Ltd.

Vitamin K antagonist control in patients with atrial fibrillation in Asia compared with other regions of the world: Real-world data from the GARFIELD-AF registry.

OBJECTIVE: To compare the distribution of international normalized ratios (INRs) in patients receiving vitamin K antagonist (VKA) for newly diagnosed atrial fibrillation in Eastern and Southeastern Asia and in other regions of the world (ORW) represented in the ongoing, global observational study GARFIELD-AF. METHODS AND RESULTS: 3621 and 13,541 patients were recruited prospectively in 2010-2013 from Asia and ORW, respectively. At baseline, excluding patients with unknown antithrombotic treatment, 1356 (37.8%) in Asia and 7081 (53.3%) in ORW received VKA (±antiplatelets). INR readings during 1-year follow-up were analyzed for VKA-treated patients with ≥3 measurements (878 [64.7%] patients in Asia, 4452 [62.9%] in ORW). VKA-treated patients in Asia were younger than those in ORW (mean 67.1 vs 71.3years), with a lower CHA2DS2-VASc score (3.0 vs 3.5), but a similar HAS-BLED score (1.3 vs 1.4). Mean INR was lower in Asia than in ORW (2.0 vs 2.4). The proportion of time in the therapeutic range, defined using the multinational target of 2.0-3.0, was substantially lower in Asia (31.1% vs 54.1%). In Asia and ORW, 59.3% and 28.2% of INRs were <2, and 9.6% and 17.7% were >3, respectively. The same trend was found in different age groups (<65, 65-74, ≥75years). CONCLUSION: GARFIELD-AF data demonstrate a difference in the distribution of INRs in patients from Asia versus other regions under current real-world practice. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: 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.