Search

Oral anticoagulation (OAC) reduces the risk of thromboembolic events in patients with atrial fibrillation (AF); however, thromboembolism (TE) still can occur despite OAC. Factors associated with residual risk for stroke, systemic embolism, or transient ischemic attack events despite OAC have not been well described.The purpose of this study was to evaluate the residual risk of thromboembolic events in patients with AF despite OAC.A total of 18,955 patients were analyzed in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF I and II) using multivariable Cox proportional hazard modeling. Mean age was 72 ± 10.7, and 42% were women. There were 451 outcome events.The risk of TE despite OAC increased with CHAPatients with AF have a residual risk of TE with increasing CHA

Low dose direct acting oral anticoagulants (LDDOACS) were approved for elderly atrial Fibrillation (AF) patients with limited information. A retrospective analysis collecting baseline characteristics and outcomes in AF patients ≥ 80 prescribed LDDOAC or warfarin (W), from a multidisciplinary practice between 1/1/11 (First LDDOAC available) and 5/31/17 was conducted. From 9660 AF patients, 514 ≥ 80 received a LDDOAC and 422 W. A multivariable comparison found LDDOAC patients were older (p0.001), had lower creatinine clearance (CrCl) (p = 0.006), used more anti-platelet drugs (p0.001), and more often had new onset AF verses those prescribed W (p0.001). There were no clinically significant differences among those patients receiving Dabigatran 75 mgs BID (D), Rivaroxaban 15mgs (R) or Apixaban 2.5mgs BID (A). Forty-eight and 50% of the patients remained on their LDDOAC or W for the observation period (p = 0.55). Stroke/systemic embolism (SSE) and CNS bleeds were 1.16 vs 2.22%/yr., (p = 0.143) and 1.46 vs 0.93%/yr., (p = 0.24). Mortality and major bleeds were 6.26 vs 1.67%/yr., and 12.3vs 3.77%/yr. (p0.001). SSE were 1.1%/yr for D, R, and A (p = 0.94). CNS bleeds were 2.2 for D, 1.7 for R and 0.8%/yr. for A: p = 0.53. Major bleeding was: 14.3 for D, 14.1 for R and 9.1%/yr. for A, p = 0.048 (with AR, p = 0.01). Mortality was 5.5 for D, 4.2 for R and 9.5% for A, p = 0.031. In conclusion, half the patients remained on their assigned anti-coagulant. SSE and intracranial bleed rates were similar and low. Major bleeds and deaths were different between groups emphasizing the need for prospective randomized trials in this growing population with AF.

Aims Using a pre-planned post hoc analysis of patients included in X-VeRT, we evaluated predictors of sinus rhythm at 6 weeks after planned cardioversion. Methods and results Receiver operating characteristic curves and logistic regression models were used to evaluate continuous and categorical variables as predictors of sinus rhythm 6 at weeks from cardioversion (end of study). The primary analysis was performed in successfully cardioverted patients with an evaluable electrocardiogram at end of study. A second analysis evaluated additional patients who spontaneously restored sinus rhythm before planned cardioversion. Of the 1504 patients with atrial fibrillation of >48 h or of unknown duration who were randomly assigned to either rivaroxaban or vitamin K antagonist, 1039 (64.6 ± 10.3 years, 73.4% male) underwent planned cardioversion and were included in this study. Patients receiving early cardioversion (i.e. between 1 and 5 days from hospitalization) had a 67% higher probability to have sinus rhythm at end of study than those who received delayed cardioversion (i.e. between 21 and 56 days from hospitalization) [odds ratio (OR) 1.67, confidence interval (CI) 1.27–2.18; P Conclusion In X-VeRT, early cardioversion and high CHADS2 scores predicted sinus rhythm at 6 weeks from cardioversion.

Background The coronavirus SARS-CoV-2 is highly contagious. Hydroxychloroquine (HCQ) has in vitro activity against SARS-CoV-2. The FDA authorized emergency use of HCQ against COVID-19. HCQ may have dose-related cardiotoxicity. This clinical trial received ethical approval on May 15, 2020, operationalized in June to evaluate a low prophylaxis dose of HCQ (200mg BID) in household contacts of COVID-19-positive patients without physical contact between investigators and participants. It represents the first report of the FDA approved 6-lead EKGs with a smartphone KardiaMobile® 6L application. Methods To reach a sample size of 170, household members were contacted by telephone, emailed consent forms with electronic signature capability, and randomized 2:1 to HCQ or observation for 10 days with follow-up of 14 days. Home saliva PCR tests recorded COVID status on days 1 and 14. Symptoms and 6-lead EKGs were obtained daily. Results Fifty-one participants were randomized with 42 evaluable at day 14. Remote monitoring of 407 EKGs revealed no QTc prolongation or other ECG changes in either group. At time of consent, no participants were symptomatic or COVID+. On days 1 and 14, COVID tests were positive in 4 and 2 in the HCQ group and 4 and 0 in the observation group. No tests converted to positive. There were no deaths or hospitalizations. Conclusions A clinical trial without personal contact, rapidly initiated and operationalized to exclude cardiac toxicity using daily remote 6-lead EKG monitoring, is feasible. Of 407 EKGs from 42 participants, there was no evidence of cardiac toxicity. Clinical trial registration Clinicaltrials.gov: NCT04652648 registration date: December 3, 2020

Aims The global COVID-19 pandemic is caused by the SARS-CoV-2 virus entering human cells using angiotensin-converting enzyme 2 (ACE2) as a cell surface receptor. ACE2 is shed to the circulation, and a higher plasma level of soluble ACE2 (sACE2) might reflect a higher cellular expression of ACE2. The present study explored the associations between sACE2 and clinical factors, cardiovascular biomarkers, and genetic variability. Methods and results Plasma and DNA samples were obtained from two international cohorts of elderly patients with atrial fibrillation (n = 3999 and n = 1088). The sACE2 protein level was measured by the Olink Proteomics® Multiplex CVD II96 × 96 panel. Levels of the biomarkers high-sensitive cardiac troponin T (hs-cTnT), N-terminal probrain natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), C-reactive protein, interleukin-6, D-dimer, and cystatin-C were determined by immunoassays. Genome-wide association studies were performed by Illumina chips. Higher levels of sACE2 were statistically significantly associated with male sex, cardiovascular disease, diabetes, and older age. The sACE2 level was most strongly associated with the levels of GDF-15, NT-proBNP, and hs-cTnT. When adjusting for these biomarkers, only male sex remained associated with sACE2. We found no statistically significant genetic regulation of the sACE2 level. Conclusions Male sex and clinical or biomarker indicators of biological ageing, cardiovascular disease, and diabetes are associated with higher sACE2 levels. The levels of GDF-15 and NT-proBNP, which are associated both with the sACE2 level and a higher risk for mortality and cardiovascular disease, might contribute to better identification of risk for severe COVID-19 infection.

BACKGROUND: The inflammatory biomarker interleukin-6 (IL-6) is associated with mortality in atrial fibrillation (AF). OBJECTIVE: To investigate if repeated IL-6 measurements improve the prognostication for stroke or systemic embolism, major bleeding, and mortality in anticoagulated patients with AF. METHODS: IL-6 levels by ELISA were measured at study entry and at 2 months in 4830 patients in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial with 1.8 years median follow-up. In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, IL-6 was measured at study entry, 3, 6, and 12 months in 2559 patients with 2.0 years median follow-up. Associations between a second IL-6 measurement and outcomes, adjusted for baseline IL-6, clinical variables, and other cardiovascular biomarkers, were analyzed by Cox regression. RESULTS: Median IL-6 levels were 2.0 ng/L (interquartile range [IQR] 1.30-3.20) and 2.10 ng/L (IQR 1.40-3.40) at the two time-points in ARISTOTLE, and, in RE-LY, 2.5 ng/L (IQR 1.6-4.3), 2.5 ng/L (IQR 1.6-4.2), 2.4 ng/L (IQR 1.6, 3.9), and 2.4 ng/L (IQR 1.5, 3.9), respectively. IL-6 was associated with mortality; hazard ratios per 50% higher IL-6 at 2 or 3 months, respectively, were 1.32 (95% confidence interval, 1.23-1.41; P

BackgroundCardioversion is common among patients with atrial fibrillation (AF). We hypothesised that novel oral anticoagulants (NOAC) used in clinical practice resulted in similar rates of stroke compared with vitamin K antagonists (VKA) for cardioversion.MethodsUsing the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II, patients with AF who had a cardioversion, follow-up data and an AF diagnosis within 6 months of enrolment were identified retrospectively. Clinical outcomes were compared for patients receiving a NOAC or VKA for 1 year following cardioversion.ResultsAmong 13 004 patients with AF, 2260 (17%) underwent cardioversion. 1613 met the inclusion criteria for this analysis. At the time of cardioversion, 283 (17.5%) were receiving a VKA and 1330 (82.5%) a NOAC. A transoesophageal echocardiogram (TOE) was performed in 403 (25%) cardioversions. The incidence of stroke/transient ischaemic attack (TIA) at 30 days was the same for patients having (3.04 per 100 patient-years) or not having (3.04 per 100 patient-years) a TOE (p=0.99). There were no differences in the incidence of death (HR 1.19, 95% CI 0.62 to 2.28, p=0.61), cardiovascular hospitalisation (HR 1.02, 95% CI 0.76 to 1.35, p=0.91), stroke/TIA (HR 1.18, 95% CI 0.30 to 4.74, p=0.81) or bleeding-related hospitalisation (HR 1.29, 95% CI 0.66 to 2.52, p=0.45) at 1 year for patients treated with either a NOAC or VKA.ConclusionsCardioversion was a low-risk procedure for patients treated with NOAC, and there were statistically similar rates of stroke/TIA 30 days after cardioversion as for patients treated with VKA. There were no statically significant differences in death, stroke/TIA or major bleeding at 1 year among patients treated with NOAC compared with VKA after cardioversion.

Aims Data on patient characteristics, prevalence, and outcomes of atrial fibrillation (AF) patients without traditional risk factors, often labelled ‘lone AF’, are sparse. Methods and results The RE-LY AF registry included 15 400 individuals who presented to emergency departments with AF in 47 countries. This analysis focused on patients without traditional risk factors, including age ≥60 years, hypertension, coronary artery disease, heart failure, left ventricular hypertrophy, congenital heart disease, pulmonary disease, valve heart disease, hyperthyroidism, and prior cardiac surgery. Patients without traditional risk factors were compared with age- and region-matched controls with traditional risk factors (1:3 fashion). In 796 (5%) patients, no traditional risk factors were present. However, 98% (779/796) had less-established or borderline risk factors, including borderline hypertension (130–140/80–90 mmHg; 47%), chronic kidney disease (eGFR 30; 19%), diabetes (5%), excessive alcohol intake (>14 units/week; 4%), and smoking (25%). Compared with patients with traditional risk factors (n = 2388), patients without traditional risk factors were more often men (74% vs. 59%, P Conclusion Almost all patients without traditionally defined AF risk factors have less-established or borderline risk factors. These patients have a favourable 1-year prognosis, but risk of AF-related re-hospitalization remains high. Greater emphasis should be placed on recognition and management of less-established or borderline risk factors.

Aims To determine the extent of shared decision-making (SDM), during selection of oral anticoagulant (OAC) and rhythm control treatments, in patients with newly diagnosed atrial fibrillation (AF). Methods and results We evaluated survey data from 1006 patients with new-onset AF enrolled at 56 US sites participating in the SATELLITE substudy of the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT II). Patients completed surveys at enrolment and at 6-month follow-up. Patients were asked about who made their AF treatment decisions. Shared decision-making was classified as one that the patient felt was an autonomous decision or a shared decision with their healthcare provider (HCP). Approximately half of patients reported that their OAC treatment decisions were made entirely by their HCP. Compared with those reporting no SDM, patients reporting SDM for OAC were more often female (47.2% vs. 38.4%), while patients reporting SDM for rhythm control were more often male (62.2% vs. 57.6%). The most important factors cited by patients during decision-making for OAC were reducing stroke and bleeding risk, and their HCP’s recommendations. After adjustment, patients with self-reported understanding of OAC, and rhythm control options, had higher odds of having participated in SDM [odds ratio (OR) 2.54, confidence interval (CI): 1.75–3.68 and OR 2.36, CI: 1.50–3.71, both P ≤ 0.001, respectively]. Conclusion Shared decision-making is not widely implemented in contemporary AF practice. Patient understanding about available therapeutic options is associated with a more than a two-fold higher likelihood of SDM, and may be a potential target for future interventions.

Aims A J-shaped association of cardiovascular events to achieved systolic (SBP) and diastolic (DBP) blood pressure was shown in high-risk patients. This association on oral anticoagulation is unknown. This analysis from RELY assessed the risks of death, stroke or systemic emboli, and bleeding according to mean achieved SBP and DBP in atrial fibrillation on oral anticoagulation. Methods and results RE-LY patients were followed for 2 years and recruited between 22 December 2005 until 15 December 2007. 18.113 patients were randomized in 951 centres in 54 countries and 18,107 patients with complete blood pressure (BP) data were analysed with a median follow-up of 2.0 years and a complete follow-up in 99.9%. The association between achieved mean SBP and DBP on all-cause death, stroke and systemic embolic events (SSE), major, and any bleeding were explored. On treatment, SBP >140 mmHg and 130 mmHg. Similar patterns were observed for DBP with an increased risk at 90 mmHg (HR 1.88; 1.43–2.46) for all-cause death compared to 70 to Conclusion Low achieved SBP associates with increased risk of death, SSE, and bleeding in patients with atrial fibrillation on oral anticoagulation. Major bleeding events did not occur at higher BP. Low BP might identify high-risk patients not only for death but also for high bleeding risks. Clinical trial registration ClinicalTrials.gov—Identifier: NCT00262600.

Background Obstructive sleep apnea (OSA) is a known risk factor for atrial fibrillation (AF). However, it remains unclear whether OSA is independently associated with worse cardiovascular and neurological outcomes in patients with AF. Methods We used the ORBIT-AF I and ORBIT-AF II to conduct a retrospective cohort study of 22,760 patients with AF with and without OSA. Adjusted multivariable Cox proportional hazards models was used to determine whether OSA was associated with increased risk for major adverse cardiac and neurologic events (MACNEs) (cardiovascular death, myocardial infarction, stroke/transient ischemic attack/non–central nervous system embolism (stroke/SE), and new-onset heart failure], combined and individually. Results A total of 4,045 (17.8%) patients had OSA at baseline. Median follow-up time was 1.5 (interquartile range: 1-2.2) years, and 1,895 patients experienced a MACNE. OSA patients were younger (median [interquartile range] 68 [61-75] years vs 74 [66-81] years), were more likely male (70.7% vs 55.3%), and had increased body mass index (median 34.6 kg/m2 [29.8-40.2] vs 28.7 kg/m2 [25.2-33.0]). Those with OSA had a higher prevalence of concomitant comorbidities such as diabetes, chronic obstructive pulmonary disease, and heart failure. OSA patients had higher use of antithrombotic therapy. After adjustment, the presence of OSA was significantly associated with MACNE (hazard ratio: 1.16 [95% CI: 1.03-1.31], P = .011). OSA was also an independent risk factor for stroke/SE beyond the CHA2DS2-VASc risk factors (HR: 1.38 [95% CI 1.12-1.70], P = .003) but not cardiovascular death, myocardial infarction, new-onset heart failure, or major bleeding. Conclusions Among patients with AF, OSA is an independent risk factor for MACNE and, more specifically, stroke/SE.

Background Comorbidities are common in patients with atrial fibrillation (AF) and affect prognosis, yet are often undertreated. However, contemporary rates of use of guideline-directed therapies (GDT) for non-AF comorbidities and their association with outcomes are not well described. Methods We used the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF) to test the association between GDT for non-AF comorbidities and major adverse cardiac or neurovascular events (MACNE; cardiovascular death, myocardial infarction, stroke/thromboembolism, or new-onset heart failure), all-cause mortality, new-onset heart failure, and AF progression. Adjustment was performed using Cox proportional hazards models and logistic regression. Results Only 6,782 (33%) of the 20,434 patients eligible for 1 or more GDT for non-AF comorbidities received all indicated therapies. Use of all comorbidity-specific GDT was highest for patients with hyperlipidemia (75.6%) and lowest for those with diabetes mellitus (43.1%). Use of “all eligible” GDT was associated with a nonsignificant trend toward lower rates of MACNE (HR 0.90 [0.79-1.02]) and all-cause mortality (HR 0.90 [0.80-1.01]). Use of GDT for heart failure was associated with a lower risk of all-cause mortality (HR 0.77 [0.67-0.89]), and treatment of obstructive sleep apnea was associated with a lower risk of AF progression (OR 0.75 [0.62-0.90]). Conclusions In AF patients, there is underuse of GDT for non-AF comorbidities. The association between GDT use and outcomes was strongest in heart failure and obstructive sleep apnea patients where use of GDT was associated with lower mortality and less AF progression.

Background The World Health Organization declared the outbreak of SARS-CoV-2 a pandemic on February 11, 2020. This organism causes COVID-19 disease and the rapid rise in cases and geographic spread strained healthcare systems. Clinical research trials were hindered by infection control measures discouraging physical contact and diversion of resources to meet emergent requirements. The need for effective treatment and prevention of COVID-19 prompted an untested investigational response. Trial groups adapted approaches using remote enrolment and consenting, newly developed diagnostic tests, delivery of study medications and devices to participants’ homes, and remote monitoring to ensure investigator/enrollee safety while preserving ethical integrity, confidentiality, and data accuracy. Methods Clinical researchers at our community health system in the USA undertook an outpatient randomized open-label study of hydroxychloroquine (HCQ) prophylaxis versus observation of SARS-CoV-2 infection in household COVID-19 contacts. Designed in March 2020, challenges included COVID-19 infection in the research group, HCQ shortage, and lack of well-established home SARS-CoV-2 tests and remote ECG monitoring protocols in populations naive to these procedures. The study was written, funded, and received ethical committee approval in 4 months and was completed by September 2020 during a period of fluctuating infection rates and conflicting political opinions on HCQ use; results have been published. Singular methodology included the use of a new RNA PCR saliva SARS-CoV-2 home diagnostic test and a remote smartphone-based 6-lead ECG recording system. Results Of 483 households contacted regarding trial participation, 209 (43.3%) did not respond to telephone calls/e-mails and 90 (18.6%) declined; others were not eligible by inclusion or exclusion criteria. Ultimately, 54 individuals were enrolled and 42 completed the study. Numbers were too small to determine the efficacy of HCQ prophylaxis. No serious treatment-related adverse events were encountered. Conclusions Flexibility in design, a multidisciplinary research team, prompt cooperation among research, funding, ethics review groups, and finding innovative study approaches enabled this work. Concerns were balancing study recruitment against unduly influencing individuals anxious for protection from the pandemic and exclusion of groups based on lack of Internet access and technology. An issue to address going forward is establishing research cooperation across community health systems before emergencies develop. Trial registration ClinicalTrials.govNCT04652648. Registered on December 3, 2020.

Glenn N. Levine, MD, FACC, FAHA, Chair Patrick T. O’Gara, MD, MACC, FAHA, Chair-Elect Jonathan L. Halperin, MD, FACC, FAHA, Immediate Past Chair [#][1] Sana M. Al-Khatib, MD, MHS, FACC, FAHA Joshua A. Beckman, MD, MS, FAHA Kim K. Birtcher, PharmD, MS, AACC Biykem Bozkurt, MD, PhD, FACC

Systolic blood pressure (SBP) and its association with clinical outcomes in atrial fibrillation (AF) patients in community practice are poorly characterized. In patients with AF, we sought to (1) examine the prevalence of baseline uncontrolled hypertension and the overall change in SBP control, (2) identify predictors of uncontrolled SBP over 2 years of follow-up, and (3) determine the relation between SBP and clinical outcomes. We analyzed 10,132 patients with AF at 176 clinics in the ORBIT-AF registry between 2010 and 2014, classified as: (1) no history of hypertension; (2) controlled hypertension (baseline SBP140 mm Hg); (3) and uncontrolled hypertension (baseline SBP140 mm Hg). Predictors of SBP140 mm Hg at baseline or in follow-up were identified with pooled logistic regression. Random effects Cox regression models were used to compare cardiovascular outcomes and major bleeding as a function of continuous, time-dependent SBP. Overall 8,383 (83%) of patients with AF had hypertension. Of these, 24.2% (n = 2032) had uncontrolled baseline SBP, with little change over 2 years. Predictors of elevated follow-up SBP included uncontrolled baseline SBP, females, previous percutaneous coronary intervention, and diabetes. For every 5 mm Hg increase in follow-up SBP, the adjusted risk of stroke or systemic embolism or transient ischemic attack (adjusted hazard ratio [aHR] 1.05, 95% confidence interval [CI] 1.01 to 1.08, p = 0.01), myocardial infarction (aHR 1.05, 95% CI 1.00 to 1.11, p = 0.04), and major bleeding (aHR 1.03, 95% CI 1.00 to 1.06, p = 0.04) increased modestly. In conclusion, in patients with AF, higher SBP was associated with increasing adverse events; therefore, more rigorous blood pressure control should be emphasized.

Aims Hospitalizations are common among patients with atrial fibrillation. This article aimed to analyse the causes and consequences of hospitalizations occurring during the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial. Methods and results The RE-LY database was used to evaluate predictors of hospitalization using multivariate regression modelling. The relationship between hospitalization and subsequent major adverse cardiac events was evaluated in a time dependent Cox proportional-hazard modelling. Of the 18 113 patients in RE-LY, 7200 (39.8%) were hospitalized at least once during a mean follow-up of 2 years. First hospitalization rates were 2312 (39.5%) for dabigatran etexilate (DE) 110, 2430 (41.6%) for DE 150, and 42.6% (N = 2458) for warfarin. Hospitalization was associated with post-discharge death [absolute event rate 9.1% vs. 2.2%; adjusted hazard ratio (HR) 3.6, 95% confidence interval (CI) 3.2–4.0, P Conclusion Hospitalizations are associated an increased risk of with death and cardiovascular death in patients with atrial fibrillation.

Aims Atrial fibrillation (AF) is associated with higher mortality. Biomarkers may improve the understanding of key pathophysiologic processes in AF that lead to death. Using a new multiplex analytic technique, we explored the association between 268 biomarkers and cardiovascular (CV) death in anticoagulated patients with AF. Methods and results A case-cohort design with 1.8 -1.9 years follow-up. The identification cohort included 517 cases and 4057 randomly selected patients from ARISTOTLE. The validation cohort included 277 cases and 1042 randomly selected controls from RE-LY. Plasma collected at randomization was analyzed with conventional immunoassays and the OLINK proximity extension assay-panels; CVDII, CVDIII, and Inflammation. Association between biomarkers and CV-death was evaluated using Random Survival Forest, Boruta and adjusted Cox-regression analyses.The biomarkers most strongly and consistently associated with CV-death were (hazard ratio for inter-quartile comparison [95% CI]): N-terminal pro-B-type natriuretic peptide (NT-proBNP; 1.63 [1.37-1.93]), cardiac troponin T (cTnT-hs; 1.60[1.35-1.88]), interleukin-6 (IL-6; 1.29[1.13-1.47]), growth differentiation factor-15 (GDF-15; 1.30[1.10-1.53]) fibroblast growth factor 23 (FGF-23; 1.21[1.10-1.33]), urokinase receptor (uPAR; 1.38[1.16-1.64]), trefoil factor 3 (TFF3; 1.27[1.10-1.46]), tumor necrosis factor receptor 1 (TNFR1; 1.21[1.01-1.45]), TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2; 1.18[1.04-1.34]) and cathepsin L1 (CTSL1; 1.22[1.07-1.39]). Conclusion In this comprehensive screening of 268 biomarkers in anticoagulated patients with AF the underlying mechanisms most strongly associated with CV-death were cardiorenal dysfunction (NT-proBNP, cTnT-hs, CTSL1, TFF3), oxidative stress (GDF-15), inflammation (IL-6, GDF-15), calcium balance, vascular and renal dysfunction (FGF-23), fibrinolysis (suPAR) and apoptosis (TNFR1, TRAILR2). These findings provide novel insights into pathophysiologic aspects associated with CV-death in AF. Translational perspective In patients with AF there is an unmet need for better understanding of the pathophysiological processes involved with CV-death. Using a targeted proteomic approach, 10 biomarkers were identified as having a strong association with CV-death. The identified biomarkers reflect several biological pathways involved with CV-death in AF. The present study provides valuable insights into important processes involved with CV-death in patients with AF and may facilitate the identification of important risk factors for death, thus allowing for earlier intervention and possibly even for targeted therapy to reduce AF-related mortality. Clinicaltrials.gov identifier NCT00412984 and NCT00262600.

Introduction: Dronedarone (DR), a P-gp and CYP 3A4 inhibitor may increase exposure and the risk of bleeding when combined with direct oral anticoagulants (DOACs). Objective: To examine the association between concomitant use of DR and the DOACs, apixaban (A), dabigatran (D), and rivaroxaban (R), and risk of bleeding compared to DOAC monotherapy in patients with atrial fibrillation (AF). Methods: A retrospective cohort study using a U.S. claims database, Truven Health MarketScan identified new users of A, D, and R in patients with AF ≥18 years from Jan 1, 2007 to Sep 30, 2017. Bleeding was defined as hospitalization or emergency room visit with a primary diagnosis of gastrointestinal (GI) bleeding, intracranial hemorrhage (ICH), or bleeding at other sites. Risk of overall and by type of bleeding was examined in concomitant users of DOAC and DR compared to patients using DOAC alone after adjusting for covariates of interest and applying propensity score (PS) trimming via Cox proportional hazards modeling. Results: Among concomitant users of DR and A (1,932), D (3,117), and R (2,395), crude incidence rates of bleeding per 1,000 person-years were 17.2, 37.8, 61.8, respectively versus 26.8, 31.3, and 44.9 in users of A (51,420), D (42,312), and R (57,300) alone. Incidence rates stratified by PS showed higher bleeding incidence in concomitant users of DR with D or R, but not with A. No increased bleeding risk was associated with use of DR and A vs A alone [Adjusted Hazard ratio (aHR): 0.69 (95% CI: 0.40, 1.17), p=0.16]. A modestly increased risk of GI bleeding but not overall bleeding was associated with combined use of DR and D vs D alone [aHR bleeding: 1.18 (95% CI: 0.89, 1.56), p=0.26; aHR GI bleeding: 1.40 (95% CI: 1.01, 1.93); p=0.04]. An increased risk of overall bleeding, driven by GI bleeding, was associated with combined use of DR and R vs R alone [aHR bleeding:1.31 (95% CI: 1.01, 1.69); p=0.04; aHR GI bleeding:1.39 (95% CI: 0.98, 1.95); p=0.06]. There was no increase in the risk of ICH associated with combined use of DR and any DOAC. Conclusions: Concomitant treatment with DR and A showed no increased risk of bleeding, but DR increased the risk of GI bleeding when given with D or R, and of overall bleeding only with R. Concomitant treatment with DR and any DOAC did not increase ICH risk.

Background: The very elderly and those receiving low doses of the direct-acting oral anticoagulants (DOACs) were underrepresented in trials leading to the approval of Apixaban 2.5 mgs BID (A), Rivaroxaban 15mgs daily (R) and Edoxaban 30 mgs daily (E). Approval of dabigatran 75mgs BID (D) was based entirely on pharmacokinetic studies. Methods: Retrospective analysis of the electronic medical record of a multi-disciplinary practice of 396,064 patients between 1/1/11 (when first DOAC available) and 5/31/17. Results: 9,446 patients had Atrial Fibrillation (AF), with 2,660 prescribed a DOAC and 846 at the low dose with 514 ≥ 80 yrs (range 80 – 98) with a mean CHA 2 DS 2 -VASc score of 4.5, which did not differ between patients prescribed D, R or A (p = 0.66 by ANOVA). Fifty-three patients received D, first used on 2/26/11, 223 R, first used on 12/15/11, and 236 A, first used on 6/19/12, and one patient received E. Among 28 baseline variables there were no clinically relevant differences among D, R, and A. All outcomes were reported as time to first event. All-cause mortality, n = 5 (5.5%/yr) for D, n =15 (4.2%) for R, and n = 23 (9.5%) for A, p = 0.031 by log rank test (with A > R by pairwise log-rank, p = 0.013). Major bleeding n = 13 (14.3%/yr) for D, n = 50 (14.1%) for R, and n = 22 (9.1%) for A, p = 0.048 by log rank test (with A < R, p = 0.017). Intracranial bleeding n = 2 (2.2%/yr) for D, n = 6 (1.7%) for R, and n = 2 (0.8%) for A, p = 0.53. There were 7 ischemic strokes or systemic embolic events (SSE) in total (1.1%/yr): D, R, and A (p = 0.94). Comparisons involving D may be underpowered. 245 patients (47.7%) remained on their prescribed drug without an event for the observation period (p = 0.55). Conclusion: D, R and A were well tolerated in patients ≥ 80 yrs, with low SSE and intracranial bleed rates. Major bleeds were the most frequent outcome, lowest in patients prescribed A. A had a higher all-cause mortality.

Key Points Question Is the recently developed ABC (age, biomarkers, and clinical history)–bleeding risk score for patients with atrial fibrillation (AF) useful to identify patients with different risks of bleeding during concomitant aspirin and anticoagulation therapy? Findings This cohort study examined a total of 24 349 patients with AF from 2 randomized clinical trials and found that the ABC-bleeding risk score identified patients with different risks of bleeding when combining aspirin and oral anticoagulation. Meaning The ABC-bleeding risk score may be a useful tool for decision support concerning intensity and duration of combination antithrombotic treatment in patients with AF and coronary artery disease., This cohort study evaluates whether the ABC (age, biomarkers, and clinical history)–bleeding risk score might be useful to identify patients with atrial fibrillation (AF) who have different risks of bleeding during concomitant aspirin and anticoagulation therapy., Importance Most patients with atrial fibrillation (AF) and coronary artery disease have indications for preventing stroke with oral anticoagulation therapy and preventing myocardial infarction and stent thrombosis with platelet inhibition. Objective To evaluate whether the recently developed ABC (age, biomarkers, and clinical history)–bleeding risk score might be useful to identify patients with AF with different risks of bleeding during concomitant aspirin and anticoagulation therapy. Design, Setting, and Participants The biomarkers in the ABC-bleeding risk score (growth differentiation factor 15, hemoglobin, and troponin) were measured in blood samples collected at randomization between 2006 and 2010 in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial and between 2005 and 2009 in the RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial, both of which were multinational randomized clinical trials. The trials were reported 2011 and 2009, respectively. A total of 24 349 patients with AF (14 980 patients from the ARISTOTLE trial and 9369 patients from the RE-LY trial) were analyzed in the present cohort study. The median (interquartile range) length of follow-up was 1.8 (1.3-2.3) years in the ARISTOTLE cohort and 2.0 (1.6-2.3) years in the RE-LY cohort. Data analysis was performed from February 2018 to June 2019. Exposures Concomitant aspirin treatment during study follow-up. Main Outcomes and Measures Time to first occurrence of a major bleeding was determined according to International Society on Thrombosis and Hemostasis definition. Hazard ratios were estimated with Cox models adjusted for ABC-bleeding risk score and randomized treatment. Results The median (interquartile range) age was 70 (63-76) years in the ARISTOTLE cohort and 72 (67-77) years in the RE-LY cohort (5238 patients [35.6%] in the ARISTOTLE cohort and 3086 patients [36.4%] in the RE-LY cohort were women). The total number of patients with a first major bleeding event was 651 (207 with aspirin and 444 without) in ARISTOTLE and 463 (238 with aspirin and 225 without) in RE-LY. For both cohorts, in those with a low ABC-bleeding risk score, the absolute bleeding rate was low even with concomitant aspirin treatment, whereas in those with a higher ABC-bleeding risk score, the rate of bleeding was higher with concomitant aspirin compared with oral anticoagulation alone (ARISTOTLE, hazard ratio, 1.65; 95% CI, 1.40-1.95; P

AIMS Patients with atrial fibrillation (AF) and rheumatic heart disease (RHD), especially mitral stenosis, are assumed to be at high risk of stroke, irrespective of other factors. We aimed to re-evaluate stroke risk factors in a contemporary cohort of AF patients. METHODS AND RESULTS We analyzed data of 15,400 AF patients presenting to an emergency department and who were enrolled in the global RE-LY AF registry, representing 47 countries from all inhabited continents. Follow-up occurred at 1 year after enrollment. A total of 1,788 (11.6%) patients had RHD. These patients were younger (51.4 ± 15.7 vs. 67.8 ± 13.6 years), more likely to be female (66.2% vs. 44.7%) and had a lower mean CHA2DS2-VASc score (2.1 ± 1.7 vs. 3.7 ± 2.2) as compared to patients without RHD (all p

Background: Atrial fibrillation (AF) adversely impacts health-related quality of life (hrQoL). While some patients demonstrate improvements in hrQoL, the factors associated with large improvements in hrQoL are not well described. Methods: We assessed factors associated with a 1-year increase in the Atrial Fibrillation Effect on Quality-of-Life score of 1 SD (≥18 points; 3× clinically important difference), among outpatients in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation I registry. Results: Overall, 28% (181/636) of patients had such a hrQoL improvement. Compared with patients not showing large hrQoL improvement, they were of similar age (median 73 versus 74, P =0.3), equally likely to be female (44% versus 48%, P =0.3), but more likely to have newly diagnosed AF at baseline (18% versus 8%; P =0.0004), prior antiarrhythmic drug use (52% versus 40%, P =0.005), baseline antiarrhythmic drug use (34.8% versus 26.8%, P =0.045), and more likely to undergo AF-related procedures during follow-up (AF ablation: 6.6% versus 2.0%, P =0.003; cardioversion: 12.2% versus 5.9%, P =0.008). In multivariable analysis, a history of alcohol abuse (adjusted OR, 2.41; P =0.01) and increased baseline diastolic blood pressure (adjusted OR, 1.23 per 10-point increase and >65 mm Hg; P =0.04) were associated with large improvements in hrQoL at 1 year, whereas patients with prior stroke/transient ischemic attack, chronic obstructive pulmonary disease, and peripheral arterial disease were less likely to improve ( P Conclusions: In this national registry of patients with AF, potentially treatable AF risk factors are associated with large hrQoL improvement, whereas less reversible conditions appeared negatively associated with hrQoL improvement. Understanding which patients are most likely to have large hrQoL improvement may facilitate targeting interventions for high-value care that optimizes patient-reported outcomes in AF. Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01165710.

Introduction This X-VeRT (eXplore the efficacy and safety of once-daily oral riVaroxaban for the prevention of caRdiovascular events in patients with nonvalvular aTrial fibrillation scheduled for cardioversion) substudy evaluated the effects of treatment with rivaroxaban or a vitamin-K antagonist (VKA) on levels of biomarkers of coagulation (D-dimer, thrombin–antithrombin III complex [TAT] and prothrombin fragment [F1.2]) and inflammation (high sensitivity C-reactive protein [hs-CRP] and high-sensitivity interleukin-6 [hs-IL-6]) in patients with atrial fibrillation (AF) who were scheduled for cardioversion and had not received adequate anticoagulation at baseline (defined as, in the 21 days before randomization: no oral anticoagulant; international normalized ratio Methods Samples for biomarker analysis were taken at baseline (n = 958) and treatment completion (42 days after cardioversion; n = 918). The influence of clinical characteristics on baseline biomarker levels and the effect of treatment on changes in biomarker levels were evaluated using linear and logistic models. Results Baseline levels of some biomarkers were significantly associated with type of AF (D-dimer and hs-IL-6) and with history of congestive heart failure (hs-CRP, D-dimer, and hs-IL-6). Rivaroxaban and VKA treatments were associated with reductions from baseline in levels of D-dimer (−32.3 and −37.6%, respectively), TAT (−28.0 and −23.1%, respectively), hs-CRP (−12.5 and −17.9%, respectively), and hs-IL-6 (−9.2 and −9.8%, respectively). F1.2 levels were reduced from baseline in patients receiving a VKA (−53.0%) but not in those receiving rivaroxaban (2.7%). Conclusion Anticoagulation with rivaroxaban reduced levels of key inflammation and coagulation biomarkers to a similar extent as VKAs, with the exception of F1.2. Further investigation to confirm the value of these biomarkers in patients with AF is merited.

Background: Bleeding is commonly cited as a reason for stopping oral anticoagulants (OACs). Whether minor bleeding events (nuisance bleeding, NB) in patients with atrial fibrillation on OACs are associated with OAC discontinuation, major bleeding, and stroke/systemic embolism (SSE) is unknown. Methods: Within the ORBIT-AF prospective, outpatient registry (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation), we identified 6771 patients ≥18 years of age at 172 sites with atrial fibrillation and eligible follow-up visits. NB was ascertained from the medical record and was defined as minor bleeding that did not require medical attention (eg, bruising, hemorrhoidal bleeding). We used multivariable pooled logistic regression modeling to evaluate the associations between NB and major bleeding and SSE in the 180 days after documentation of NB. Our unit of analysis was the patient visit, occurring at ≈6-month intervals for a median of 1.5 years following enrollment. Changes in anticoagulation treatment satisfaction after NB were examined descriptively in a subset of patients. Results: The median age of the overall population was 75.0 (interquartile range, 67.0–81.0); 90.0% were white and 42.5% were female. Among 6771 patients (18 560 visits), n=1357 (20.0%) had documented NB, for an incidence rate of 14.8 events per 100 person-years. Over 96.4% of patients remained on OAC therapy after the NB event. Overall, 287 (4.3%) patients experienced major bleeding and 64 (0.96%) had a SSE event during follow-up. NB was not associated with a significant increased risk of major bleeding over 6 months in models adjusting for the ATRIA bleeding score (Anticoagulation and Risk Factors in Atrial Fibrillation) (odds ratio, 1.04; 95% confidence interval, 0.68–1.60; P =0.86). NB was also not associated with increased SSE risk over 6 months in models adjusting for the CHA 2 DS 2 -VASc risk score (odds ratio, 1.24; 95% confidence interval, 0.53–2.91; P =0.62). Conclusions: NB is common among patients with atrial fibrillation on OACs. However, NB was not associated with a higher risk of major bleeding or SSE over the next 6 months, suggesting its occurrence should not lead to changes in anticoagulation treatment strategies in OAC-treated patients. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01165710.

Anticoagulation is highly effective for the prevention of stroke in patients with atrial fibrillation (AF) but it is dependent on patients continuing therapy. While studies have demonstrated suboptimal therapeutic persistence on warfarin, few have studied persistence rates with non vitamin K antagonist oral anticoagulants (NOACs) such as dabigatran. We examined rates of continued use of dabigatran versus warfarin over 1 year among AF patients in the ORBIT-AF registry between June 29, 2010 and August 09, 2011. Multivariable logistic regression analysis was used to identify characteristics associated with 1-year persistent use of dabigatran therapy or warfarin. At baseline, 6.4 and 93.6% of 7150 AF patients were on dabigatran and warfarin, respectively. At 12 months, dabigatran-treated patients were less likely to have continued their therapy than warfarin-treated patients [Adjusted persistence rates: 66% (95% CI 60–72) vs. 82% (95% CI 80–84), p

Aim The primary objective was to compare apixaban to heparin/vitamin K antagonist (VKA) in patients with atrial fibrillation (AF) and ≤48 h anticoagulation prior to randomization undergoing cardioversion. Methods One thousand five hundred patients were randomized. The apixaban dose of 5 mg b.i.d. was reduced to 2.5 mg b.i.d. in patients with two of the following: age ≥ 80 years, weight ≤ 60 kg, or serum creatinine ≥ 133 µmol/L. To expedite cardioversion, at the discretion of the investigator, imaging and/or a loading dose of 10 mg (down-titrated to 5 mg) was allowed. The endpoints for efficacy were stroke, systemic embolism (SE), and death. The endpoints for safety were major bleeding and clinically relevant non-major (CRNM) bleeding. Results There were 1038 active and 300 spontaneous cardioversions; 162 patients were not cardioverted. Imaging was performed in 855 patients, and 342 received a loading dose of apixaban. Comparing apixaban to heparin/VKA in the full analysis set, there were 0/753 vs. 6/747 strokes [relative risk (RR) 0; 95% confidence interval (95% CI) 0-0.64; nominal P = 0.015], no SE, and 2 vs. 1 deaths (RR 1.98; 95% CI 0.19-54.00; nominal P > 0.999). In the safety population, there were 3/735 vs. 6/721 major (RR 0.49; 95% CI 0.10-2.07; nominal P = 0.338) and 11 vs. 13 CRNM bleeding events (RR 0.83; 95% CI 0.34-1.89; nominal P = 0.685). On imaging, 60/61 with thrombi continued randomized treatment; all (61) were without outcome events. Conclusions Rates of strokes, systemic emboli, deaths, and bleeds were low for both apixaban and heparin/VKA treated AF patients undergoing cardioversion. Clinical trials.gov number NCT02100228.

Different oral anticoagulants may be associated with gastrointestinal bleeding (GIB) from different locations or mucosal lesions. We aimed to test this hypothesis. Two blinded gastroenterologists independently analyzed source documents from the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial of dabigatran 150 mg BID (D150), dabigatran 110 mg BID (D110) versus warfarin in non-valvular atrial fibrillation (NVAF). Major GIB events (total n = 546) and life-threatening GIB events (n = 258) were more common with D150 versus warfarin (RR 1.57 [1.28–1.92] and RR 1.62 [1.20–2.18], respectively) and similar for D110 compared to warfarin (RR 1.11 [0.89–1.38] and RR 1.16 [0.84–1.61], respectively). Fatal bleeding was similarly rare across treatment groups. Lower GI major bleeding and life-threatening bleeding were more common with D150 compared to warfarin (RR 2.23 [1.47, 3.38] and RR 2.64 [1.36, 5.13], respectively) and with D110 compared to warfarin (RR 1.78 [1.16, 2.75] and RR 2.00 [1.00, 4.00], respectively). MGIB from colonic angiodysplasia was increased with dabigatran versus warfarin (P

Aims: In atrial fibrillation (AF), mortality remains high despite effective anticoagulation. A model predicting the risk of death in these patients is currently not available. We developed and validated a risk score for death in anticoagulated patients with AF including both clinical information and biomarkers. Methods and results: The new risk score was developed and internally validated in 14 611 patients with AF randomized to apixaban vs. warfarin for a median of 1.9 years. External validation was performed in 8548 patients with AF randomized to dabigatran vs. warfarin for 2.0 years. Biomarker samples were obtained at study entry. Variables significantly contributing to the prediction of all-cause mortality were assessed by Cox-regression. Each variable obtained a weight proportional to the model coefficients. There were 1047 all-cause deaths in the derivation and 594 in the validation cohort. The most important predictors of death were N-terminal pro B-type natriuretic peptide, troponin-T, growth differentiation factor-15, age, and heart failure, and these were included in the ABC (Age, Biomarkers, Clinical history)-death risk score. The score was well-calibrated and yielded higher c-indices than a model based on all clinical variables in both the derivation (0.74 vs. 0.68) and validation cohorts (0.74 vs. 0.67). The reduction in mortality with apixaban was most pronounced in patients with a high ABC-death score. Conclusion: A new biomarker-based score for predicting risk of death in anticoagulated AF patients was developed, internally and externally validated, and well-calibrated in two large cohorts. The ABC-death risk score performed well and may contribute to overall risk assessment in AF.

To evaluate and validate the prognostic value of growth-differentiation factor 15 (GDF-15) beyond clinical characteristics and other biomarkers concerning bleeding and stroke outcomes in patients with atrial fibrillation in the RE-LY trial.GDF-15 was measured in samples collected at randomization in 8,474 patients with a median follow-up time of 1.9 years. Patients were stratified based on predefined GDF-15 cutoffs: group 1,1,200 ng/L (the 90th percentile in healthy individuals); group 2, 1,200-1,800; and group 3,1,800 ng/L (high-risk individuals). Efficacy and safety outcomes were compared across groups of GDF-15 in Cox models adjusted for baseline characteristics, cardiac (N-terminal pro-b-type natriuretic peptide, high-sensitive troponin T), inflammatory (interleukin 6, C-reactive protein) and coagulation (D-dimer) biomarkers, and randomized treatment.GDF-15 concentrations were1,200 ng/L in 2,647 (31.2%), between 1,200 and 1,800 ng/L in 2,704 (31.9%), and1,800 ng/L in 3,123 (36.9%) participants, respectively. Annual rates of stroke, major bleeding, and mortality increased with higher GDF-15 levels. The prognostic value of GDF-15 was independent of clinical characteristics for these outcomes. In models also adjusted for biomarkers, GDF-15 remained significantly associated with major bleeding (hazard ratio [95% CI] group 3 vs group 1 1.76 [1.28-2.42], P.0005) and all-cause mortality (hazard ratio 1.72 [1.30-2.29], P.0005). GDF-15 improved the c index of both the HAS-BLED (0.62-0.69) and ORBIT (0.68-0.71) bleeding risk scores.In patients with atrial fibrillation, GDF-15 is an independent risk indicator for major bleeding and all-cause mortality, but not for stroke. Therefore, GDF-15 seems useful as a specific marker of bleeding in patients with AF on oral anticoagulant treatment.

Aim We tested the hypothesis that left ventricular hypertrophy (LVH) interferes with the antithrombotic effects of dabigatran and warfarin in patients with atrial fibrillation (AF). Methods and results This is a post-hoc analysis of the Randomized Evaluation of Long-term anticoagulation therapY (RE-LY) Study. We defined LVH by electrocardiography (ECG) and included patients with AF on the ECG tracing at entry. Hazard ratios (HR) for each dabigatran dose vs. warfarin were calculated in relation to LVH. LVH was present in 2353 (22.7%) out of 10 372 patients. In patients without LVH, the rates of primary outcome were 1.59%/year with warfarin, 1.60% with dabigatran 110 mg (HR vs. warfarin 1.01, 95% confidence interval (CI) 0.75–1.36) and 1.08% with dabigatran 150 mg (HR vs. warfarin 0.68, 95% CI 0.49–0.95). In patients with LVH, the rates of primary outcome were 3.21%/year with warfarin, 1.69% with dabigatran 110 mg (HR vs. warfarin 0.52, 95% CI 0.32–0.84) and 1.55% with 150 mg (HR vs. warfarin 0.48, 95% CI 0.29–0.78). The interaction between LVH status and dabigatran 110 mg vs. warfarin was significant for the primary outcome (P = 0.021) and stroke (P = 0.016). LVH was associated with a higher event rate with warfarin, not with dabigatran. In the warfarin group, the time in therapeutic range was significantly lower in the presence than in the absence of LVH. Conclusions LVH was associated with a lower antithrombotic efficacy of warfarin, but not of dabigatran, in patients with AF. Consequently, the relative benefit of the lower dose of dabigatran compared to warfarin was enhanced in patients with LVH. The higher dose of dabigatran was superior to warfarin regardless of LVH status. Clinical trial registration http:www.clinicaltrials.gov. Unique identifier: NCT00262600.

Background & Aims Gastrointestinal (GI) bleeding in patients receiving anticoagulation agents can be caused by occult malignancies. We investigated the proportions and features of major GI bleeding (MGIB) events related to occult GI cancers in patients receiving anticoagulation therapy. Methods We analyzed data from the Randomized Evaluation of Long Term Anticoagulant Therapy study (conducted between December 2005 and March 2009 in 951 clinical centers in 44 countries worldwide), which compared the abilities of dabigatran vs warfarin to prevent stroke and systemic embolism in 18,113 patients with atrial fibrillation. Two blinded gastroenterologists independently reviewed source documents of MGIB events (n = 595) that occurred during the study period. We collected data on MGIB events caused by previously unidentified GI malignancies, and compared characteristics of MGIB events in patients who received dabigatran vs warfarin (primary end point), and in patients with bleeding from cancer, vs patients bleeding from a nonmalignant or unidentified source. Results Of 546 unique MGIB events, 44 (8.1%) were found to be from GI cancers (34 of 398 MGIB events in dabigatran users and 10 of 148 MGIB events in warfarin users; P = .60). Colorectal cancer accounted for 35 of 44 of all cancers identified. There were more colorectal cancer–associated MGIB events in the dabigatran group (30 of 34) than in the warfarin group (5 of 10) (P = .02), but more gastric cancer–associated MGIB events in the warfarin group (5 of 10) than in the dabigatran group (1 of 34) (P = .001). There were no differences in the short-term outcomes of cancer-related MGIB events in the dabigatran vs the warfarin group, but 75% of all cancer-related MGIB events required at least 1 blood transfusion and the mean hospital stay was 10.1 days. Compared with MGIB events from a nonmalignant or unidentified source, MGIB from cancer occurred sooner (343.0 vs 223.1 d; P = .003), but the bleeding was more likely to be chronic (for >7 d) (27.3% vs 63.6%; P Conclusions In evaluating data from a study of the effects of anticoagulation therapy, we found approximately 1 of every 12 MGIB events to be related to an occult cancer. Approximately two thirds of cancer-related MGIB presents with chronic bleeding, and morbidity, and resource utilization is high.

Background The Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire has recently been validated to measure the impact of atrial fibrillation on quality of life, but a clinically important difference in AFEQT score has not been well defined. Methods and Results To determine the clinically important difference in overall AFEQT (score range= 0 [worst] to 100 [best]) and selected subscales, we analyzed data in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry, a United States-based outpatient atrial fibrillation registry. AFEQT was assessed at baseline and 1 year in a subset of 1347 ORBIT-AF patients from 80 US sites participating in ORBIT-AF from June 2010 to August 2011. The mean change method was used to relate changes in 1-year AFEQT scores to clinically important changes in the physician assessment of European Heart Rhythm Association functional status (1 class improvement and separately 1 class deterioration). Clinically important differences and 95% CI corresponding to either a 1 European Heart Rhythm Association class improvement or deterioration were 5.4 (3.6-7.2) and -4.2 (-6.9 to -1.5) AFEQT points, respectively. Similarly, clinically important difference values were seen for a 1 European Heart Rhythm Association class improvement for the AFEQT subscales Activities of Daily Living and Symptoms: 5.1 (2.5-7.6) and 7.1 (5.3-9.0) AFEQT points, respectively. Conclusions Based on the anchor of 1 European Heart Rhythm Association class change, changes in AFEQT score of + or -5 points are clinically important changes in patients' health. Clinical Trial Registration URL: https://clinicaltrials.gov . Unique identifier: NCT01165710.

Introduction: Shared decision making (SDM) incorporates patient and physician values and preferences into treatment selection. While multiple therapeutic options are available for stroke prevention in atrial fibrillation (AF), few studies have examined factors associated with SDM regarding choice of antithrombotic strategy. Methods: We evaluated survey data from 1006 patients with new-onset AF enrolled at 56 sites participating in a substudy of the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT II), an outpatient AF registry in the US. Patients were asked: “When choosing your blood thinner(s), who made this treatment decision?”, and SDM was defined as a response of “equally me and my healthcare provider (HCP)”, “mostly me” or “entirely me”, while no SDM was defined as a response of “mostly my HCP” or “entirely my HCP”. Multivariable logistic regression models evaluated associations between 13 patient-level factors, self-reported understanding of treatment options, and SDM for antithrombotic therapy. Results: Most patients allowed their HCP to make the therapeutic decisions on antithrombotic strategy, with 246 (24.5%) reporting SDM. Patients reporting SDM were more often female (47.2% vs. 40.5%) and were more frequently insured by Medicare (40.2% vs. 34.5%) than patients reporting no SDM. Among patients taking warfarin, median time in therapeutic range was higher among patients reporting SDM than among those not reporting SDM. In multivariable models, chronic obstructive pulmonary disease was associated with lower odds of SDM while self-reported understanding of blood thinner options was associated with higher odds of SDM (Table). Conclusion: One in four patients in an outpatient AF registry reported that their current antithrombotic strategy was the result of a shared decision making process. Additional work is need to determine whether patient-reported SDM is associated with medication adherence and outcomes of therapy.

Background Cardiac biomarkers and left ventricular hypertrophy ( LVH ) are related to the risk of stroke and death in patients with atrial fibrillation. We investigated the interrelationship between LVH and cardiac biomarkers and their independent associations with outcomes. Methods and Results Plasma samples were obtained at baseline in 5275 patients with atrial fibrillation in the RE ‐ LY (Randomized Evaluation of Long‐Term Anticoagulation Therapy) trial. NT ‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), cardiac troponin I and T, and growth differentiation factor‐15 were determined using high‐sensitivity (hs) assays. LVH was defined by ECG . Cox models were adjusted for baseline characteristics, LVH , and biomarkers. LVH was present in 1257 patients. During a median follow‐up of 2.0 years, 165 patients developed a stroke and 370 died. LVH was significantly ( P NT ‐pro BNP , 1.32 (1.25–1.38); hs cardiac troponin I, 1.67 (1.57–1.78); hs troponin T, 1.38 (1.32–1.44); and growth differentiation factor‐15, 1.09 (1.05–1.12). For stroke, the hazard ratios (95% CIs) per 50% increase were as follows: NT ‐pro BNP, 1.09 (1.00–1.19); hs cardiac troponin I, 1.09 (1.03–1.15); hs troponin T, 1.14 (1.06–1.24); and growth differentiation factor‐15, 1.22 (1.08–1.38) (all P NT ‐pro BNP , 1.24 (1.17–1.31); hs cardiac troponin I, 1.13 (1.10–1.17); hs troponin T, 1.28 (1.23–1.34); and growth differentiation factor‐15, 1.31 (1.22–1.42) (all P LVH was not significantly associated with stroke or death after adjustment for biomarkers. Conclusions Cardiac biomarkers are significantly associated with LVH . The prognostic value of biomarkers for stroke and death is not affected by LVH . The prognostic information of LVH is attenuated in the presence of cardiac biomarkers. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00262600.

ObjectivesGrowth differentiation factor 15 (GDF-15) is a biomarker independently associated with bleeding and death in anticoagulated patients with atrial fibrillation (AF). GDF-15 is also used as one component in the more precise biomarker-based ABC (age, biomarkers, clinical history)-AF-bleeding and ABC-AF-death risk scores. Data from large trials indicate a geographic variability in regard to overall outcomes, including bleeding and mortality risk. Our aim was to assess the consistency of the association between GDF-15, ABC-AF-bleeding score and ABC-AF-death score, with major bleeding and death, across world geographic regions.MethodsData were available from 14 767 patients with AF from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial and 8651 patients with AF from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial in this cohort study. GDF-15 was analysed from plasma samples obtained at randomisation. The geographical consistency of the associations between outcomes and GDF-15, ABC-AF-bleeding score and ABC-AF-death scores were assessed by Cox-regression models including interactions with predefined geographical region.ResultsGDF-15 and the ABC-AF-bleeding score were associated with major bleeding in both trials across regions (pConclusionsIn patients with AF on anticoagulation, GDF-15 and the biomarker-based ABC-AF-bleeding and ABC-AF-death risk scores are consistently associated with respectively increased risk of major bleeding and death and have similar prognostic value across world geographic regions.Trial registration numberClinicalTrials.gov Registry NCT00412984 and NCT00262600.

Summary Background Atrial fibrillation is an important cause of morbidity and mortality worldwide, but scant data are available for long-term outcomes in individuals outside North America or Europe, especially in primary care settings. Methods We did a cohort study using a prospective registry of patients in 47 countries who presented to a hospital emergency department with atrial fibrillation or atrial flutter as a primary or secondary diagnosis. 15 400 individuals were enrolled to determine the occurrence of death and strokes (the primary outcomes) in this cohort over eight geographical regions (North America, western Europe, and Australia; South America; eastern Europe; the Middle East and Mediterranean crescent; sub-Saharan Africa; India; China; and southeast Asia) 1 year after attending the emergency department. Patients from North America, western Europe, and Australia were used as the reference population, and compared with patients from the other seven regions Findings Between Dec 24, 2007, and Oct 21, 2011, we enrolled 15 400 individuals to the registry. Follow-up was complete for 15 361 (99·7%), of whom 1758 (11%) died within 1 year. Fewer deaths occurred among patients presenting to the emergency department with a primary diagnosis of atrial fibrillation compared with patients who had atrial fibrillation as a secondary diagnosis (377 [6%] of 6825 patients vs 1381 [16%] of 8536, p Interpretation Marked unexplained inter-regional variations in the occurrence of stroke and mortality suggest that factors other than clinical variables might be important. Prevention of death from heart failure should be a major priority in the treatment of atrial fibrillation. Funding Boehringer Ingelheim.

Background: The RE-LY trial (Randomized Evaluation of Long-Term Anticoagulant Therapy) compared dabigatran 150 and 110 mg twice daily with warfarin in 18 113 patients with atrial fibrillation. Those with prosthetic heart valves, significant mitral stenosis, and valvular heart disease (VHD) requiring intervention were excluded. Others with VHD were included. Methods: This is a post hoc analysis of the RE-LY trial. Results: There were 3950 patients with any VHD: 3101 had mitral regurgitation, 1179 with tricuspid regurgitation, 817 had aortic regurgitation, 471 with aortic stenosis, and 193 with mild mitral stenosis. At baseline, patients with any VHD had more heart failure, coronary disease, renal impairment, and persistent atrial fibrillation. Patients with any VHD had higher rates of major bleeds (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.16–1.5) but similar stroke or systemic embolism event rates (HR, 1.09; 95% CI, 0.88–1.33). For patients receiving dabigatran 110 mg, major bleed rates were lower than for patients taking warfarin (HR, 0.73; 95% CI, 0.56–0.95 with VHD; HR, 0.84; 95% CI, 0.71–0.99 without VHD), and major bleed rates for dabigatran 150 mg were similar to those for warfarin in patients with VHD (HR, 0.82; 95% CI, 0.64–1.06) or without VHD (HR, 0.98; 95% CI, 0.83–1.15). For dabigatran 150 mg, stroke/systemic embolic event rates were lower compared with warfarin in those with VHD (HR, 0.59; 95% CI, 0.37–0.93) and those without VHD (HR, 0.67; 95% CI, 0.52–0.86), and stroke/systemic embolic event rates were similar for warfarin and dabigatran 110 mg regardless of the presence of VHD (HR, 0.97; 95% CI, 0.65–1.45; and HR, 0.88; 95% CI, 0.70–1.10). Intracranial bleeds and death rates for dabigatran 150 and 110 mg were lower compared with warfarin independently of the presence of VHD. Conclusions: The presence of any VHD did not influence the comparison of dabigatran with warfarin. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00262600.

Summary Background The benefit of oral anticoagulation in atrial fibrillation is based on a balance between reduction in ischaemic stroke and increase in major bleeding. We aimed to develop and validate a new biomarker-based risk score to improve the prognostication of major bleeding in patients with atrial fibrillation. Methods We developed and internally validated a new biomarker-based risk score for major bleeding in 14 537 patients with atrial fibrillation randomised to apixaban versus warfarin in the ARISTOTLE trial and externally validated it in 8468 patients with atrial fibrillation randomised to dabigatran versus warfarin in the RE-LY trial. Plasma samples for determination of candidate biomarker concentrations were obtained at randomisation. Major bleeding events were centrally adjudicated. The predictive values of biomarkers and clinical variables were assessed with Cox regression models. The most important variables were included in the score with weights proportional to the model coefficients. The ARISTOTLE and RE-LY trials are registered with ClinicalTrials.gov, numbers NCT00412984 and NCT00262600, respectively. Findings The most important predictors for major bleeding were the concentrations of the biomarkers growth differentiation factor-15 (GDF-15), high-sensitivity cardiac troponin T (cTnT-hs) and haemoglobin, age, and previous bleeding. The ABC-bleeding score (age, biomarkers [GDF-15, cTnT-hs, and haemoglobin], and clinical history [previous bleeding]) score yielded a higher c-index than the conventional HAS-BLED and the newer ORBIT scores for major bleeding in both the derivation cohort (0·68 [95% CI 0·66–0·70] vs 0·61 [0·59–0·63] vs 0·65 [0·62–0·67], respectively; ABC-bleeding vs HAS-BLED p vs ORBIT p=0·0008). ABC-bleeding score also yielded a higher c-index score in the the external validation cohort (0·71 [95% CI 0·68–0·73] vs 0·62 [0·59–0·64] for HAS-BLED vs 0·68 [0·65–0·70] for ORBIT; ABC-bleeding vs HAS-BLED p vs ORBIT p=0·0016). A modified ABC-bleeding score using alternative biomarkers (haematocrit, cTnI-hs, cystatin C, or creatinine clearance) also outperformed the HAS-BLED and ORBIT scores. Interpretation The ABC-bleeding score, using age, history of bleeding, and three biomarkers (haemoglobin, cTn-hs, and GDF-15 or cystatin C/CKD-EPI) was internally and externally validated and calibrated in large cohorts of patients with atrial fibrillation receiving anticoagulation therapy. The ABC-bleeding score performed better than HAS-BLED and ORBIT scores and should be useful as decision support on anticoagulation treatment in patients with atrial fibrillation. Funding BMS, Pfizer, Boehringer Ingelheim, Roche Diagnostics.

The North American Thrombosis Forum Atrial Fibrillation Action Initiative consensus document is a comprehensive yet practical briefing document focusing on stroke and bleeding risk assessment in patients with atrial fibrillation, as well as recommendations regarding anticoagulation options and management. Despite the breadth of clinical trial data and guideline recommendation updates, many clinicians continue to struggle to synthesize the disparate information available. This problem slows the uptake and utilization of updated risk prediction tools and adoption of new oral anticoagulants. This document serves as a practical and educational reference for the entire medical community involved in the care of patients with atrial fibrillation.

The early repolarization (ER) pattern (ERP), initially described as elevation of the ST segment of ≥1 leads on the 12-lead ECG, has long been considered a benign phenomenon. However, more recent studies have demonstrated positive, negative, and neutral associations between an ERP and various end points, including all-cause, cardiac, and arrhythmic mortality. These recent studies have used more complex or heterogeneous definitions of ER, including J-wave or J-point elevation and QRS complex notching or slurring, with or without concomitant ST-segment elevation. Other studies have identified an increased prevalence of ERP in survivors of spontaneous ventricular fibrillation (VF) or cardiac arrest. As a result, considerable confusion remains concerning the definition of ERP, its prognostic significance, and whether additional evaluation or treatment is warranted. These issues are especially important because the prevalence of ERP may be as high as 10% in the general population and even higher in some healthy subgroups. The writing group performed a comprehensive literature search and developed recommendations based on the results of the current literature. We searched MEDLINE (via PubMed), EMBASE, and the Cochrane Library to identify relevant primary scientific articles, guideline statements, and review articles in the literature. Search terms included, but were not limited to, early repolarization, J-point elevation, J wave, Haissaguerre syndrome, sudden cardiac death, idiopathic ventricular fibrillation, ventricular fibrillation, cardiac repolarization reserve, sudden unexplained death syndrome, and Osborn waves. We also reviewed the references of highly cited documents and citing documents. The recommendations were voted on, and 80% agreement was required for inclusion. The purposes of this document are as follows