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Background: Direct oral anticoagulants are the standard of care for stroke prevention in eligible patients with atrial fibrillation and atrial flutter; however, bleeding remains a significant concern, limiting their use. Milvexian is an oral Factor XIa inhibitor that may offer similar anticoagulant efficacy with less bleeding risk., Methods: LIBREXIA AF (NCT05757869) is a global phase III, randomized, double-blind, parallel-group, event-driven trial to compare milvexian with apixaban in participants with atrial fibrillation or atrial flutter. Participants are randomly assigned to milvexian 100 mg or apixaban (5 mg or 2.5 mg per label indication) twice daily. The primary efficacy objective is to evaluate if milvexian is noninferior to apixaban for the prevention of stroke and systemic embolism. The principal safety objective is to evaluate if milvexian is superior to apixaban in reducing the endpoint of International Society of Thrombosis and Hemostasis (ISTH) major bleeding events and the composite endpoint of ISTH major and clinically relevant nonmajor (CRNM) bleeding events. In total, 15,500 participants from approximately 1,000 sites in over 30 countries are planned to be enrolled. They will be followed until both 430 primary efficacy outcome events and 530 principal safety events are observed, which is estimated to take approximately 4 years., Conclusion: The LIBREXIA AF study will determine the efficacy and safety of the oral Factor XIa inhibitor milvexian compared with apixaban in participants with either atrial fibrillation or atrial flutter., Trial Registration: ClinicalTrials.gov NCT05757869., Competing Interests: Disclosures SSJ reports consulting fees from Bristol Myers Squibb, ARTIS Ventures, and Broadview Ventures outside of the submitted work. KWM’s financial disclosures can be reviewed at http://med.stanford.edu/profiles/kenneth-mahaffey. KSP is a member of The Thrombosis Research Institute which has received institutional research grant support from Anthos Therapeutics and Bayer Pharmaceuticals. She has received honoraria from Element Science and Artivion, Inc. WS has received honoraria (>10K USD) from Daiichi Sankyo, Nippon Boehringer Ingelheim, and Pfizer Japan, and research grants (>50K USD) from Daiichi Sankyo and Nippon Boehringer Ingelheim. CTR reports Research Grants through Institution from: Athos, AstraZeneca, Daiichi Sankyo, Janssen and Novartis. Honoraria for scientific ad boards and consulting from: Anthos, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Janssen and Pfizer. He is a member of The TIMI Study Group which has received institutional research grant support through Brigham and Women's Hospital from: Abbott, Abiomed, Inc, Amgen, Anthos Therapeutics, ARCA Biopharma, Inc, AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Ionis Pharmaceuticals, Inc, Janssen Research & Development, LLC, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc, Roche, Saghmos Therapeutics, Inc, Siemens Healthcare Diagnostics, Inc, Softcell Medical Limited, The Medicines Company, Verve Therapeutics, Inc, Zora Biosciences. PRK reports consultancy from Anthos, J&J, BMS and Bayer. GS has received research grants from Amarin, AstraZeneca, and Sanofi; has participated in clinical trials, consulting, or speaking for Amarin, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Idorsia, Janssen, Novartis, Novo Nordisk, PhaseBio, Pfizer, and Sanofi; is a Senior Associate Editor at Circulation; and serves as the CMO for Bioquantis. RM reports institutional research payments from: Abbott, Affluent Medical, Alleviant Medical, Amgen, AstraZeneca, BAIM, Beth Israel Deaconess Medical Center, Boston Scientific, Bristol-Myers Squibb, CardiaWave, CERC, Chiesi, Concept Medical, Daiichi Sankyo, Duke, Faraday, Idorsia, Janssen, MedAlliance, Medscape, Mediasphere, Medtelligence, Medtronic, Novartis, OrbusNeich, Pi-Cardia, Protembis, RM Global Bioaccess Fund Management, Sanofi; consultant to Affluent Medical, Boehringer Ingelheim, Chiesi USA, Cordis, Esperion Science/Innovative Biopharma, Gaffney Events, Educational Trust, Global Clinical Trial Partners, Ltd., IQVIA, Medscape/WebMD Global, NovoNordisk, PeerView Institute for Medical Education, TERUMO Europe N.V., Radcliffe and honoararia from AMA and ACC. SCJ has received research support from Jansen, BMS, and AstraZeneca. GJH reports personal honoraria outside the submitted work from the American Heart Association (Associate Editor, Circulation), Bristol Myers Squibb (Steering Committee, AXIOMATIC-SSP trial of milvexian [factor XIa inhibitor] for secondary stroke prevention) and Janssen (Co-chair, Executive Committee, Librexia Stroke trial of milvexian for secondary stroke prevention). RAH has received research grants/contracts from NHLBI (ISCHEMIA), Duke/PCORI (ADAPTABLE), Janssen (Factor Xia inhibitor), CSL (HDL), Baim Institute, UColorado, Harvard (BWH), and Merck; has served as a consultant/advisor for NHLBI (COVID/CONNECTS), Atropos Health, Bitterroot Bio, Bristol Myers Squibb, Bridge Bio, Chiesi, CSL Behring, Edwards Lifesciences Corp, Element Science, Foresight, Merck, and WebMD; and serves on the Board of Directors for AHA and Cytokinetics. CSPL is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has Received research support from Novo Nordisk and Roche Diagnostics; has Served as consultant or on the Advisory Board/ Steering Committee/ Executive Committee for Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Hanmi, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd., Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics and Us2.ai; and serves as Co-founder and nonexecutive director of Us2.ai. The remaining authors report no relevant disclosures or competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Many patients with atrial fibrillation suffer from comorbid vascular disease. The comparative efficacy and safety of different types of oral anticoagulation (OAC) in this patient group have not been widely studied., Methods: Adults with newly diagnosed atrial fibrillation were recruited into the prospective observational registry, GARFIELD-AF, and followed for 24 months. Associations of vascular disease with clinical outcomes were analyzed using adjusted hazard ratios (HR) obtained via Cox proportional-hazard modeling. Outcomes of OAC vs no OAC, and of non-vitamin K antagonist OAC (NOAC) vs vitamin K antagonist (VKA) treatment, were compared by overlap propensity-weighted Cox proportional-hazard models., Results: Of 51,574 atrial fibrillation patients, 25.9% had vascular disease. Among eligible atrial fibrillation patients, those with vascular disease received OAC less frequently than those without (63% vs 73%). Over 2-year follow-up, patients with vascular disease showed a higher risk of all-cause mortality (HR 1.30; 95% confidence interval [CI], 1.16-1.47) and cardiovascular mortality (HR 1.59; 95% CI, 1.28-1.97). OAC was associated with a significant decrease in all-cause mortality and non-hemorrhagic stroke, and increased risk of major bleeding in non-vascular disease. In vascular disease, similar but non-significant trends existed for stroke and major bleeding. A significantly lower risk of all-cause mortality (HR 0.74; 95% CI, 0.61-0.90) and major bleeding (HR 0.45; 95% CI, 0.29-0.70) was observed in vascular disease patients treated with NOACs, compared with VKAs., Conclusions: Atrial fibrillation patients with a history of vascular disease have worse long-term outcomes than those without. The association of NOACs vs VKA with clinical outcomes was more evident in atrial fibrillation patients with vascular disease., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Investigate real-world outcomes of early rhythm versus rate control in patients with recent onset atrial fibrillation., Methods: The Global Anticoagulant Registry in the FIELD-AF (GARFIELD-AF) is an international multi-centre, non-interventional prospective registry of newly diagnosed (≤6 weeks' duration) atrial fibrillation patients at risk for stroke. Patients were stratified according to treatment initiated at baseline (≤48 days post enrolment), and outcome risks evaluated by overlap propensity weighted Cox proportional-hazards models., Results: Of 45,382 non-permanent atrial fibrillation patients, 23,858 (52.6 %) received rhythm control and 21,524 (47.4 %) rate control. Rhythm-controlled patients had lower median age (68.0 [Q1;Q3: 60.0;76.0] versus 73.0 [65.0;79.0]), fewer histories of stroke/transient ischemic attack/systemic embolism (9.4 % versus 13.0 %), and lower expected probabilities of death (median GARFIELD-AF death score 4.0 [2.3;7.5] versus 5.1 [2.8;9.2]). The two groups had the same median CHA 2 DS 2 -VASc scores (3.0 [2.0;4.0]) and similar proportions of anticoagulated patients (rhythm control: 66.0 %, rate control: 65.5 %). The propensity-score-weighted hazard ratios of rhythm vs rate control (reference) were 0.85 (95 % CI: 0.79-0.92, p-value < 0.0001) for all-cause mortality, 0.84 (0.72-0.97, p-value 0.020) for non-haemorrhagic stroke/systemic embolism and 0.90 (0.78-1.04, p-value 0.164) for major bleeding., Conclusion: Rhythm control strategy was initiated in about half of the patients with newly diagnosed non-valvular non-permanent atrial fibrillation. After balancing confounders, significantly lower risks of all-cause mortality and non-haemorrhagic stroke were observed in patients who received early rhythm control., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [The authors declare the following potential conflicts of interest: MPK is a recipient of a grant to the institution from Bayer, for support of her ASTORIA study (unrelated to the current publication). TSH reports personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Imedic, Novartis, MSD, Sanofi, and Pfizer. DA reports personal fees from Bayer, Boehringer-Ingelheim, Bristol Meier Squibb, MSD and Pfizer, and grants to the institution from Medtronic and BMS. PJ has served as a consultant or on an advisory board for Bayer, Boehringer Ingelheim, and Novartis. AJC has received institutional grant funding and personal fees from Bayer, Boehringer Ingelheim, Bristol Meier Squibb, Daiichi Sankyo, and Pfizer, and personal fees from Sanofi, Menarini, Abbot, Boston Scientific and Medtronic. AKK has received grants and personal fees from Bayer AG, and Sanofi S.A., and Anthos Therapeutics. SH has received personal fees from Bayer, BMS, Daiichi Sankyo, Pfizer, and Sanofi. SG was a recipient of quality personal fees from Jansen and Antos, and Phillips, fees from the American Heart Association as an Associate Editor for Circulation, and Steering Committee fees from Duke University. EP declares honoraria for participation in clinical trials by Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, Sanofi, AstraZeneca, Daiichi Sankyo Pharma Development, GlaxoSmithKline DMPK. She received fees for contributions to advisory boards or oral presentations from Sanofi, Bayer, Lilly, AstraZeneca, Boehringer Ingelheim, Bayer, Pfizer, Bristol-Myers Squibb, Servier, Takeda-NYCOMED, GlaxoSmithKline, MEDICINES, Aspen, and Stada. PA reports research grants to the institution from Novo Nordisk, Sanofi, and Spark Therapeutics. All other authors have reported that they have no relationships relevant to the content of this paper to disclose.]., (© 2023 The Author(s).)

Background: An unmet need exists to reliably predict the risk of intracranial hemorrhage (ICH) in patients with atrial fibrillation (AF) treated with oral anticoagulants (OACs)., Hypothesis: An externally validated model improves ICH risk stratification., Methods: Independent factors associated with ICH were identified by Cox proportional hazard modeling, using pooled data from the GARFIELD-AF (Global Anticoagulant Registry in the FIELD-Atrial Fibrillation) and ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) registries. A predictive model was developed and validated by bootstrap sampling and by independent data from the Danish National Patient Register., Results: In the combined training data set, 284 of 53 878 anticoagulated patients had ICH over a 2-year period (0.31 per 100 person-years; 95% confidence interval [CI]: 0.28-0.35). Independent predictors of ICH included: older age, prior stroke or transient ischemic attack, concomitant antiplatelet (AP) use, and moderate-to-severe chronic kidney disease (CKD). Vitamin K antagonists (VKAs) were associated with a significantly higher risk of ICH compared with non-VKA oral anticoagulants (NOACs) (adjusted hazard ratio: 1.61; 95% CI: 1.25-2.08; p = .0002). The ability of the model to discriminate individuals in the training set with and without ICH was fair (optimism-corrected C-statistic: 0.68; 95% CI: 0.65-0.71) and outperformed three previously published methods. Calibration between predicted and observed ICH probabilities was good in both training and validation data sets., Conclusions: Age, prior ischemic events, concomitant AP therapy, and CKD were important risk factors for ICH in anticoagulated AF patients. Moreover, ICH was more frequent in patients receiving VKA compared to NOAC. The new validated model is a step toward mitigating this potentially lethal complication., (© 2023 The Authors. Clinical Cardiology published by Wiley Periodicals LLC.)

Aims: This study aims to describe both management and prognosis of patients with diabetes mellitus (DM) and newly diagnosed atrial fibrillation (AF), overall as well as by antidiabetic treatment, and to assess the influence of oral anticoagulation (OAC) on outcomes by DM status., Methods: The study population comprised 52 010 newly diagnosed patients with AF, 11 542 DM and 40 468 non-DM, enrolled in the GARFIELD-AF registry. Follow-up was truncated at 2 years after enrolment. Comparative effectiveness of OAC versus no OAC was assessed by DM status using a propensity score overlap weighting scheme and weights were applied to Cox models., Results: Patients with DM [39.3% oral antidiabetic drug (OAD), 13.4% insulin ± OAD, 47.2% on no antidiabetic drug] had higher risk profile, OAC use, and rates of clinical outcomes compared with patients without DM. OAC use was associated in patients without DM and patients with DM with lower risk of all-cause mortality [hazard ratio 0.75 (0.69-0.83), 0.74 (0.64-0.86), respectively] and stroke/systemic embolism (SE) [0.69 (0.58-0.83), 0.70 (0.53-0.93), respectively]. The risk of major bleeding with OAC was similarly increased in patients without DM and those with DM [1.40 (1.14-1.71), 1.37 (0.99-1.89), respectively]. Patients with insulin-requiring DM had a higher risk of all-cause mortality and stroke/SE [1.91 (1.63-2.24)], [1.57 (1.06-2.35), respectively] compared with patients without DM, and experienced significant risk reductions of all-cause mortality and stroke/SE with OAC [0.73 (0.53-0.99); 0.50 (0.26-0.97), respectively]., Conclusions: In both patients with DM and patients without DM with AF, OAC was associated with lower risk of all-cause mortality and stroke/SE. Patients with insulin-requiring DM derived significant benefit from OAC., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: This study aimed to identify relationships in recently diagnosed atrial fibrillation (AF) patients with respect to anticoagulation status, use of guideline-directed medical therapy (GDMT) for comorbid cardiovascular conditions (co-GDMT), and clinical outcomes. The Global Anticoagulant Registry in the FIELD (GARFIELD)-AF is a prospective, international registry of patients with recently diagnosed non-valvular AF at risk of stroke (NCT01090362)., Methods and Results: Guideline-directed medical therapy was defined according to the European Society of Cardiology guidelines. This study explored co-GDMT use in patients enrolled in GARFIELD-AF (March 2013-August 2016) with CHA 2 DS 2 -VASc ≥ 2 (excluding sex) and ≥1 of five comorbidities-coronary artery disease, diabetes mellitus, heart failure, hypertension, and peripheral vascular disease ( n = 23 165). Association between co-GDMT and outcome events was evaluated with Cox proportional hazards models, with stratification by all possible combinations of the five comorbidities. Most patients (73.8%) received oral anticoagulants (OACs) as recommended; 15.0% received no recommended co-GDMT, 40.4% received some, and 44.5% received all co-GDMT. At 2 years, comprehensive co-GDMT was associated with a lower risk of all-cause mortality [hazard ratio (HR) 0.89 (0.81-0.99)] and non-cardiovascular mortality [HR 0.85 (0.73-0.99)] compared with inadequate/no GDMT, but cardiovascular mortality was not significantly reduced. Treatment with OACs was beneficial for all-cause mortality and non-cardiovascular mortality, irrespective of co-GDMT use; only in patients receiving all co-GDMT was OAC associated with a lower risk of non-haemorrhagic stroke/systemic embolism., Conclusion: In this large prospective, international registry on AF, comprehensive co-GDMT was associated with a lower risk of mortality in patients with AF and CHA 2 DS 2 -VASc ≥ 2 (excluding sex); OAC therapy was associated with reduced all-cause mortality and non-cardiovascular mortality, irrespective of co-GDMT use., Clinical Trial Registration: Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362., Competing Interests: Conflict of interest: A.J.C. has received institutional grants and personal fees from Bayer, Boehringer Ingelheim, BMS/Pfizer, and Daichi Sankyo. J.S. has received consultant and/or speaker fees from Abbott, Alexion, AstraZeneca, Bayer, Berlin-Chemie, Biosense Webster, Biotronik, Boehringer Ingelheim, Boston Scientific, BMS, Daiichi Sankyo, Medscape, Medtronic, Menarini, Merck/MSD, Organon, Pfizer, Saja, Servier, and WebMD. He reports ownership of Swiss EP and CorXL. K.A.A.F. has received grants and personal fees from Bayer/Janssen and AstraZeneca. S.Z.G. has received research support from Bayer, BMS, Boston Scientific, BTG, EKOS, Janssen, NHLBI, and Pfizer and has consultancy with Pfizer. S.G. has received a quality fee from the American Heart Association and received a steering committee fee from Duke University. S.H. has received personal fees from Bayer, BMS, Daiichi Sankyo, Pfizer, and Sanofi, outside the submitted work. A.G.G.T. has received personal fees from Bayer Healthcare, Janssen Pharmaceutical Research & Development LLC, Astellas, Portola, and Takeda. F.W.A.V. has received grants from Bayer Healthcare and personal fees from Bayer Healthcare, BMS/Pfizer, Daiichi Sankyo, and Boehringer Ingelheim. K.S.P. has consultancy with Johnson & Johnson, Element Science, Artivion, and Novartis. A.K.K. has received grants and personal fees from Bayer AG, Sanofi, and Anthos Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

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 CHA 2 DS 2 -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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The management of atrial fibrillation (AF), the most common sustained arrhythmia, impacts healthcare resource utilization (HCRU). This study aims to estimate global resource use in AF patients, using the GARFIELD-AF registry. A prospective cohort study was conducted to characterize HCRU in AF patients enrolled in sequential cohorts from 2012 to 2016 in 35 countries. Components of HCRU studied were hospital admissions, outpatient care visits, and diagnostic and interventional procedures occurring during follow-up. AF-related HCRU was reported as the percentage of patients demonstrating at least one event and was quantified as rate-per-patient-per-year (PPPY) over time. A total of 49,574 patients was analyzed, having an overall median follow-up of 719 days. Almost all patients (99.5%) had at least one outpatient care visit, while hospital admissions were the second most frequent medical contact, with similar proportions in North America (37.5%) and Europe (37.2%), and slightly higher in the other GARFIELD-AF countries (42.0%; namely Australia, Egypt, and South Africa). Asia and Latin America showed lower percentages of hospitalizations, outpatient care visits, and diagnostic and interventional procedures. Analyses of GARFIELD-AF highlighted the vast AF-related HCRU, underlying significant geographical differences in the type, quantity, and frequency of AF-related HCRU. These differences were likely attributable to health service availability and differing models of care.

Background: 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., Objective: The purpose of this study was to evaluate the residual risk of thromboembolic events in patients with AF despite OAC., Methods: 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., Results: The risk of TE despite OAC increased with CHA 2 DS 2 -VASc score: 0.76 (95% confidence interval [CI] 0.63-0.92) events per 100 patient-years for CHA 2 DS 2 -VASc score <4 vs 2.01 (95% CI 1.81-2.24) events per 100-patient years for CHA 2 DS 2 -VASc score >4. Factors associated with increased risk were previous stroke or transient ischemic attack (hazard ratio [HR] 2.87; 95% CI 2.30-3.59; P <.001), female sex (HR 1.52; 95% CI 1.24-1.86; P <.001), hypertension (HR 1.50; 95% CI 1.09-2.06; P = .01), and permanent AF (HR 1.47; 95% CI 1.12-1.94; P = .001). When transient ischemic attack was excluded, the results were similar, but permanent AF was no longer significantly associated with thromboembolic events., Conclusion: Patients with AF have a residual risk of TE with increasing CHA 2 DS 2 -VASc score despite OAC. Key risk markers include previous stroke/transient ischemic attack, female sex, hypertension, and permanent AF., (© 2022 Heart Rhythm Society. Published by Elsevier Inc.)

Aims: To determine whether the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) integrated risk tool predicts mortality, non-haemorrhagic stroke/systemic embolism, and major bleeding for up to 2 years after new-onset AF and to assess how this risk tool performs compared with CHA2DS2-VASc and HAS-BLED., Methods and Results: Potential predictors of events included demographic and clinical characteristics, choice of treatment, and lifestyle factors. A Cox proportional hazards model was identified for each outcome by least absolute shrinkage and selection operator methods. Indices were evaluated in comparison with CHA2DS2-VASc and HAS-BLED risk predictors. Models were validated internally and externally in ORBIT-AF and Danish nationwide registries. Among the 52 080 patients enrolled in GARFIELD-AF, 52 032 had follow-up data. The GARFIELD-AF risk tool outperformed CHA2DS2-VASc for all-cause mortality in all cohorts. The GARFIELD-AF risk score was superior to CHA2DS2-VASc for non-haemorrhagic stroke, and it outperformed HAS-BLED for major bleeding in internal validation and in the Danish AF cohort. In very low- to low-risk patients [CHA2DS2-VASc 0 or 1 (men) and 1 or 2 (women)], the GARFIELD-AF risk score offered strong discriminatory value for all the endpoints when compared to CHA2DS2-VASc and HAS-BLED. The GARFIELD-AF tool also included the effect of oral anticoagulation (OAC) therapy, thus allowing clinicians to compare the expected outcome of different anticoagulant treatment decisions [i.e. no OAC, non-vitamin K antagonist (VKA) oral anticoagulants, or VKAs]., Conclusions: The GARFIELD-AF risk tool outperformed CHA2DS2-VASc at predicting death and non-haemorrhagic stroke, and it outperformed HAS-BLED for major bleeding in overall as well as in very low- to low-risk group patients with AF., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier for GARFIELD-AF: NCT01090362, ORBIT-AF I: NCT01165710; ORBIT-AF II: NCT01701817., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The outcomes of patients newly diagnosed with atrial fibrillation (AF) following the introduction of direct-acting oral anticoagulants are not well known., Aim: To determine the 2-year outcomes of patients newly diagnosed with AF, and the effectiveness of oral anticoagulants in everyday practice., Design and Setting: This was a prospective observational cohort study in UK primary care., Method: In total, 3574 patients aged ≥18 years with a new AF diagnosis were enrolled. A propensity score was applied using an overlap weighting scheme to obtain unbiased estimates of the treatment effect of anticoagulation versus no anticoagulation on the occurrence of death, non-haemorrhagic stroke/systemic embolism, and major bleeding within 2 years of diagnosis., Results: Overall, 65.8% received anticoagulant therapy, 20.8% received an antiplatelet only, and 13.4% received neither. During the study period, the overall incidence rates of all-cause mortality, non-haemorrhagic stroke/systemic embolism, and major bleeding were 4.15 (95% confidence interval [CI] = 3.69 to 4.65), 1.45 (95% CI = 1.19 to 1.77), and 1.21 (95% CI = 0.97 to 1.50) per 100 person-years, respectively. Anticoagulation treatment compared with no anticoagulation treatment was associated with significantly lower all-cause mortality adjusted hazard ratio (aHR) 0.70 (95% CI = 0.53 to 0.93), significantly lower risk of non-haemorrhagic stroke/systemic embolism (aHR 0.39, 95% CI = 0.24 to 0.62), and a non-significant higher risk of major bleeding (aHR 1.31, 95% CI = 0.77 to 2.24)., Conclusion: The data support a benefit of anticoagulation in reducing stroke and death, without an increased risk of a major bleed in patients with new-onset AF. Anticoagulation treatment in patients at high risk of stroke who are not receiving anticoagulation may further improve outcomes., (© The Authors.)

Randomized controlled trials (RCTs) are considered the gold standard for estimating the effectiveness of a treatment. However, in many instances they are impractical to conduct because of time limitations, cost restrictions, or ethical reasons. As a consequence, non-randomized observational studies have an important role in comparative effectiveness and safety research since they can address issues that would not be possible using conventional RCT methodology. Observational studies can be strategically designed to reduce the risk of potential sources of bias by emulating the design principles of an equivalent but ideal randomized trial - the target trial - that would answer the research question of interest. In this article, we review some of the necessary components of observational studies required for valid causal inference within the framework of target trial emulation, so as to avoid common methodological pitfalls of study design. We discuss the assumptions of consistency, time-zero specification, exchangeability and positivity. To illustrate these concepts in a context where existing knowledge is well-established through clinical trials, we evaluate and compare the treatment effects of vitamin K antagonists (VKA) against no VKA (No VKA) on the treatment of atrial fibrillation from two real-world observational studies, namely the GARFIELD-AF and ORBIT-AF registries. Results are compared with those of published RCTs., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the clinical outcomes of patients who underwent cardioversion compared with those who did not have cardioverson in a large dataset of patients with recent onset non-valvular atrial fibrillation., Design: Observational study using prospectively collected registry data (Global Anticoagulant Registry in the FIELD-AF-GARFIELD-AF)., Setting: 1317 participating sites in 35 countries., Participants: 52 057 patients aged 18 years and older with newly diagnosed atrial fibrillation (up to six weeks' duration) and at least one investigator determined stroke risk factor., Main Outcome Measures: Comparisons were made between patients who received cardioversion and those who had no cardioversion at baseline, and between patients who received direct current cardioversion and those who had pharmacological cardioversion. Overlap propensity weighting with Cox proportional hazards models was used to evaluate the effect of cardioversion on clinical endpoints (all cause mortality, non-haemorrhagic stroke or systemic embolism, and major bleeding), adjusting for baseline risk and patient selection., Results: 44 201 patients were included in the analysis comparing cardioversion and no cardioversion, and of these, 6595 (14.9%) underwent cardioversion at baseline. The propensity score weighted hazard ratio for all cause mortality in the cardioversion group was 0.74 (95% confidence interval 0.63 to 0.86) from baseline to one year follow-up and 0.77 (0.64 to 0.93) from one year to two year follow-up. Of the 6595 patients who had cardioversion at baseline, 299 had a follow-up cardioversion more than 48 days after enrolment. 7175 patients were assessed in the analysis comparing type of cardioversion: 2427 (33.8%) received pharmacological cardioversion and 4748 (66.2%) had direct current cardioversion. During one year follow-up, event rates (per 100 patient years) for all cause mortality in patients who received direct current and pharmacological cardioversion were 1.36 (1.13 to 1.64) and 1.70 (1.35 to 2.14), respectively., Conclusion: In this large dataset of patients with recent onset non-valvular atrial fibrillation, a small proportion were treated with cardioversion. Direct current cardioversion was performed twice as often as pharmacological cardioversion, and there appeared to be no major difference in outcome events for these two cardioversion modalities. For the overall cardioversion group, after adjustments for confounders, a significantly lower risk of mortality was found in patients who received early cardioversion compared with those who did not receive early cardioversion., Study Registration: ClinicalTrials.gov NCT01090362., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from Kantor Charitable Foundation for the Kantor-Kakkar Global Centre for Thrombosis Science for the submitted work. TSH reports personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Imedic, Novartis, MSD, Sanofi, and Pfizer. JYLH reports personal fees from Bayer, BMS/Pfizer, Boehringer Ingelheim, and Daiichi-Sankyo. PJ has served as a consultant or on an advisory board for Bayer, Boehringer Ingelheim, and Novartis. RC reports research grants from Boston Scientific, Medtronic, Abbott, Pfizer, Daiichi Sankyo, Biosense Webster, Boehringer Ingelheim, Johnson and Johnson, and personal fees from Boston Scientific, Medtronic, Biosense Webster, Abbott. DA reports personal fees from Bayer, Boehringer-Ingelheim, Bristol Meier Squibb, MSD and Pfizer, and grants to the institution from Medtronic and BMS. AJC has received institutional grant funding and personal fees from Bayer, Boehringer Ingelheim, Bristol Meier Squibb, Daiichi Sankyo, and Pfizer. AKK has received grants from Bayer AG, and Sanofi, personal fees from Bayer AG, Janssen, Pfizer, Sanofi, Verseon, and Anthos Therapeutics. All other authors have reported that they have no relationships relevant to the content of this paper to disclose., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Objectives: This study evaluated the comparative effectiveness of vitamin K antagonists (VKAs), direct thrombin inhibitors (DTIs) and factor Xa inhibitors (FXaI) in patients with atrial fibrillation (AF) at risk of stroke in everyday practice., Methods: Data from patients with AF and Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke, TIA, or thromboembolism, Vascular disease, Age 65-74 years, Sex category (CHA 2 DS 2 -VASc) score ≥2 (excluding gender) in the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation registry were analysed using an improved method of propensity weighting, overlap weights and Cox proportional hazards models., Results: All-cause mortality, non-haemorrhagic stroke/systemic embolism (SE) and major bleeding over 2 years were compared in 25 551 patients, 7162 (28.0%) not treated with oral anticoagulant (OAC) and 18 389 (72.0%) treated with OAC (FXaI (41.8%), DTI (11.4%) and VKA (46.8%)). OAC treatment compared with no OAC treatment was associated with decreased risk of all-cause mortality (HR 0.82 (95% CI 0.74 to 0.91)) and non-haemorrhagic stroke/SE (HR 0.71 (95% CI 0.57 to 0.88)) but increased risk of major bleeding (HR 1.46 (95% CI 1.15 to 1.86)). Non-vitamin K antagonist oral anticoagulant (NOAC) use compared with no OAC treatment was associated with lower risks of all-cause mortality and non-haemorrhagic stroke/SE (HR 0.67 (95% CI 0.59 to 0.77)) and 0.65 (95% CI 0.50 to 0.86)) respectively, with no increase in major bleeding (HR 1.10 (95% CI 0.82 to 1.47)). NOAC use compared with VKA use was associated with lower risk of all-cause mortality and major bleeding (rates/100 patient-years 3.6 (95% CI 3.3 to 3.9) vs 4.8 (95% CI 4.5 to 5.2) and 1.0 (95% CI 0.9 to 1.1) vs 1.4 (95% CI 1.2 to 1.6); HR 0.79 (95% CI 0.70 to 0.89) and 0.77 (95% CI 0.61 to 0.98) respectively), with similar risk of non-haemorrhagic stroke/SE (rates/100 patient-years 0.8 (95% CI 0.7 to 0.9) versus 1.0 (95% CI 0.8 to 1.1); HR 0.96 (95% CI 0.73 to 1.25)., Conclusion: Important benefits in terms of mortality and major bleeding were observed with NOAC versus VKA with no difference among NOAC subtypes., Trial Registration Number: NCT01090362., Competing Interests: Competing interests: AJC has received institutional grants and personal fees from Bayer, Boehringer Ingelheim, Pfizer/BMS and Daiichi Sankyo. KAAF has received grants and personal fees from Bayer/Janssen and AstraZeneca and personal fees from Sanofi/Regeneron and Verseon outside the submitted work. DF reports personal fees from Bayer outside the submitted work. BJG reports Data Safety Monitoring Board–Mount Sinai St Luke’s, Boston Scientific Corporation, St Jude Medical Inc, Janssen Research & Development LLC, Thrombosis Research Institute, Duke Clinical Research Institute, Duke University, Kowa Research Institute Inc, Cardiovascular Research Foundation, and Medtronic and general consulting for Janssen Scientific Affairs, Xenon Pharmaceuticals and Sirtex Medical Limited. SG has received research support from BiO2 Medical, Boehringer-Ingelheim, BMS, Boston Scientific, Daiichi, Janssen, NHLBI and the Thrombosis Research Institute; has served as a consultant for, Bayer, Boehringer-Ingelheim, BMS, Daiichi and Janssen. ShG has received personal fees from the Thrombosis Research Institute, Harvard University, the American Heart Association, and grants from the Vehicle Racing Commemorative Foundation, Nakatani Foundation for Advancement of Measuring Technologies in Biomedical Engineering, Bristol-Myers Squibb, Sanofi, Ono and Pfizer. SH has received personal fees from Aspen, Bayer Healthcare, BMS/Pfizer, Daiichi-Sankyo, Portola and Sanofi. FM is an employee of Bayer AG. AGGT has received personal fees from Bayer Healthcare, Janssen Pharmaceutical Research & Development LLC, Portola. FWAV has received grants from Bayer Healthcare; personal fees from Bayer Healthcare, BMS/Pfizer, Daiichi-Sankyo, and Boehringer-Ingelheim. RC reports reports a research grants from Boston Scientific, Medtronic, Abbott, Pfizer, Daiichi Sankyo, Biosense Webster, Boehringer Ingelheim, Jhonson and Jhonson and personale fee from Boston Scientific, Medtronic, Biosense Webster, Abbott. AKK has received grants from Bayer AG and Sanofi; personal fees from Bayer AG, Janssen, Pfizer, Sanofi, Verseon and Anthos Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2021 by The American Society of Hematology.)

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).

Aims: Most clinical risk stratification models are based on measurement at a single time-point rather than serial measurements. Artificial intelligence (AI) is able to predict one-dimensional outcomes from multi-dimensional datasets. Using data from Global Anticoagulant Registry in the Field (GARFIELD)-AF registry, a new AI model was developed for predicting clinical outcomes in atrial fibrillation (AF) patients up to 1 year based on sequential measures of prothrombin time international normalized ratio (PT-INR) within 30 days of enrolment., Methods and Results: Patients with newly diagnosed AF who were treated with vitamin K antagonists (VKAs) and had at least three measurements of PT-INR taken over the first 30 days after prescription were analysed. The AI model was constructed with multilayer neural network including long short-term memory and one-dimensional convolution layers. The neural network was trained using PT-INR measurements within days 0-30 after starting treatment and clinical outcomes over days 31-365 in a derivation cohort (cohorts 1-3; n = 3185). Accuracy of the AI model at predicting major bleed, stroke/systemic embolism (SE), and death was assessed in a validation cohort (cohorts 4-5; n = 1523). The model's c-statistic for predicting major bleed, stroke/SE, and all-cause death was 0.75, 0.70, and 0.61, respectively., Conclusions: Using serial PT-INR values collected within 1 month after starting VKA, the new AI model performed better than time in therapeutic range at predicting clinical outcomes occurring up to 12 months thereafter. Serial PT-INR values contain important information that can be analysed by computer to help predict adverse clinical outcomes., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Patients with atrial fibrillation on oral anticoagulation (OAC) undergoing cardiac catheterization face risks for embolic and bleeding events, yet information on strategies to mitigate these risks in contemporary practice is lacking., Methods: We aimed to describe the clinical/procedural characteristics of a contemporary cohort of patients with atrial fibrillation on OAC who underwent cardiac catheterization. Use of bleeding avoidance strategies and bridging therapy were described and outcomes including death, stroke, and major bleeding at 30 days and 1 year were compared by OAC type., Results: Of 13 404 patients in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II Registry from 2013 to 2016, 741 underwent cardiac catheterization (139 with percutaneous coronary intervention) in the setting of OAC. The patients' median age was 71, 61.8% were male, white (87.2%), had hypertension (83.7%), hyperlipidemia (72.1%), diabetes mellitus (31.6%), and chronic kidney disease (28.2%); 20.2% received warfarin while 79.8% received direct acting oral anticoagulant. One third of patients underwent radial artery access, and bivalirudin was used in 4.6%. Bridging therapy was used more often in patients on warfarin versus direct acting oral anticoagulant (16.7% versus10.0%). OAC was interrupted in 93.8% of patients. Patients on warfarin versus direct acting oral anticoagulant were equally likely to restart OAC (58.0% versus 60.7%), had similar use of antiplatelet therapy (44.0% versus 41.3%) after catheterization, and had similar rates of myocardial infarction and death at 1 year, but higher rates of major bleeding (43.3 versus 12.9 events/100 patient years) and stroke (4.9 versus 1.9 events/100 patient years)., Conclusions: In a real-world registry of patients with atrial fibrillation undergoing cardiac catheterization, most cases are elective, performed by femoral access, with interruption of OAC. Bleeding avoidance strategies such as radial artery access and bivalirudin were used infrequently and use of bridging therapy was uncommon. Nearly 40% of patients did not restart OAC postprocedure, exposing patients to risk for stroke. Further research is necessary to optimize the management of patients with atrial fibrillation undergoing cardiac catheterization.

Background: It is not always possible to verify whether a patient complaining of symptoms consistent with transient ischemic attack has had an actual cerebrovascular event., Research Question: To characterize the risk of cardiovascular events associated with a history of stroke/transient ischemic attack in patients with atrial fibrillation., Study Design and Methods: This study investigated the clinical characteristics and outcomes of patients with a history of stroke/transient ischemic attack among 52,014 patients enrolled prospectively in GARFIELD-AF registry. The diagnosis of stroke or transient ischemic attack was not protocol defined but based on physicians' assessment. Patients' one-year risk of death, stroke/systemic embolism, and major bleeding was assessed by multivariable Cox regression., Results: At enrollment, 5617 (10.9%) patients were reported to have a history of stroke or transient ischemic attack. Patients with stroke or transient ischemic attack were older and had a greater burden of diabetes, moderate-to-severe kidney disease, and atherothrombosis and higher median CHA 2 DS 2 -VASc and HAS-BLED scores than those without history of stroke or transient ischemic attack. After adjustment, prior stroke/transient ischemic attack was associated with significantly higher risk for all-cause mortality (hazard ratio (HR), 1.26; 95% confidence interval (CI), 1.12-1.42), cardiovascular death (HR, 1.22; 95% CI, 1.01-1.48), non-cardiovascular death (HR, 1.39; 95% CI, 1.15-1.68), and stroke/systemic embolism (HR, 2.17; 95% CI, 1.80-2.63) than patients without history of stroke/transient ischemic attack. In patients with a prior stroke alone higher risk was observed for all-cause mortality (HR, 1.29; 95% CI, 1.11-1.50), non-cardiovascular death (HR, 1.39; 95% CI, 1.10-1.77), and stroke/systemic embolism (HR, 2.29; 95% CI, 1.83-2.86). No significantly elevated risk of adverse events was seen for patients with history of transient ischemic attack alone., Interpretation: A history of prior stroke or transient ischemic attack is a strong independent risk factor for mortality and stroke/systemic embolism. This excess risk is mainly attributed to a history of stroke (with or without transient ischemic attack), whereas history of transient ischemic attack is a weaker predictor. Clinical trial registration: NCT01090362.

Importance: Patients with nonvalvular atrial fibrillation at risk of stroke should receive oral anticoagulants (OAC). However, approximately 1 in 8 patients in the Global Anticoagulant Registry in the Field (GARFIELD-AF) registry are treated with antiplatelet (AP) drugs in addition to OAC, with or without documented vascular disease or other indications for AP therapy., Objective: To investigate baseline characteristics and outcomes of patients who were prescribed OAC plus AP therapy vs OAC alone., Design, Setting, and Participants: Prospective cohort study of the GARFIELD-AF registry, an international, multicenter, observational study of adults aged 18 years and older with recently diagnosed nonvalvular atrial fibrillation and at least 1 risk factor for stroke enrolled between March 2010 and August 2016. Data were extracted for analysis in October 2017 and analyzed from April 2018 to June 2019., Exposure: Participants received either OAC plus AP or OAC alone., Main Outcomes and Measures: Clinical outcomes were measured over 3 and 12 months. Outcomes were adjusted for 40 covariates, including baseline conditions and medications., Results: A total of 24 436 patients (13 438 [55.0%] male; median [interquartile range] age, 71 [64-78] years) were analyzed. Among eligible patients, those receiving OAC plus AP therapy had a greater prevalence of cardiovascular indications for AP, including acute coronary syndromes (22.0% vs 4.3%), coronary artery disease (39.1% vs 9.8%), and carotid occlusive disease (4.8% vs 2.0%). Over 1 year, patients treated with OAC plus AP had significantly higher incidence rates of stroke (adjusted hazard ratio [aHR], 1.49; 95% CI, 1.01-2.20) and any bleeding event (aHR, 1.41; 95% CI, 1.17-1.70) than those treated with OAC alone. These patients did not show evidence of reduced all-cause mortality (aHR, 1.22; 95% CI, 0.98-1.51). Risk of acute coronary syndrome was not reduced in patients taking OAC plus AP compared with OAC alone (aHR, 1.16; 95% CI, 0.70-1.94). Patients treated with OAC plus AP also had higher rates of all clinical outcomes than those treated with OAC alone over the short term (3 months)., Conclusions and Relevance: This study challenges the practice of coprescribing OAC plus AP unless there is a clear indication for adding AP to OAC therapy in newly diagnosed atrial fibrillation.

Background: Studies evaluating the effects of atrial fibrillation (AF) catheter ablation versus antiarrhythmic therapy on outcomes have shown mixed results. In addition, guidelines recommend continuing oral anticoagulation (OAC) after ablation for those at risk of stroke, but real-world data are lacking., Methods: We evaluated outcomes including death, myocardial infarction, stroke or systemic embolism, intracranial bleeding, major bleeding, and hospitalization in patients undergoing AF ablation compared with a propensity score matched cohort of patients treated with anti-arrhythmic medications only in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation registries. Cox proportional hazards regression was performed to evaluate the association between AF ablation and outcomes. We then evaluated patterns of treatment with OAC among AF ablation patients., Results: Among 21 595 patients, 1190 (6%) underwent de novo AF ablation. Our propensity score-matched cohort included 1087 patients who underwent AF ablation matched 1:1 with 1087 patients treated with antiarrhythmic medications only. There were no significant differences in the risk of all-cause and cardiovascular death, and most other major adverse cardiovascular and neurological events. AF catheter ablation was associated with an increased risk of all-cause hospitalization during follow-up (hazard ratio, 1.24 [95% CI, 1.05-1.46]), particularly in the first 3 months (the standard blanking period) after the procedure. Among those who underwent AF ablation with a CHA 2 DS 2 VASc score ≥2 for men and ≥3 for women, 23% had OAC discontinued after ablation. Among those who discontinued OAC, the median time to discontinuation was 6.2 months., Conclusions: In this large US national registry, we found no difference in adjusted rates of cardiovascular or all-cause death between patients treated with AF catheter ablation and antiarrhythmic medications only. Notably, discontinuation of OAC after ablation remains relatively common despite guideline recommendations for continued stroke prevention therapy in patients at risk of stroke.

Background: To examine the effects of the DPP-4i sitagliptin on CV outcomes during and after incident MI in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS)., Methods: TECOS randomized 14,671 participants with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD) to sitagliptin or placebo, in addition to usual care. For those who had a within-trial MI, we analyzed case fatality, and for those with a nonfatal MI, we examined a composite cardiovascular (CV) outcome (CV death or hospitalization for heart failure [hHF]) by treatment group, using Cox proportional hazards models left-censored at the time of the first within-trial MI, without and with adjustment for potential confounders, in intention-to-treat analyses., Results: During TECOS, 616 participants had ≥ 1 MI (sitagliptin group 300, placebo group 316, HR 0.95, 95% CI 0.81-1.11, P = 0.49), of which 25 were fatal [11 and 14, respectively]). Of the 591 patients with a nonfatal MI, 87 (15%) died subsequently, with 66 (11%) being CV deaths, and 57 (10%) experiencing hHF. The composite outcome occurred in 58 (20.1%; 13.9 per 100 person-years) sitagliptin group participants and 50 (16.6%; 11.7 per 100 person-years) placebo group participants (HR 1.21, 95% CI 0.83-1.77, P = 0.32, adjusted HR 1.23, 95% CI 0.83-1.82, P = 0.31). On-treatment sensitivity analyses also showed no significant between-group differences in post-MI outcomes., Conclusions: In patients with type 2 diabetes and ASCVD experiencing an MI, sitagliptin did not reduce subsequent risk of CV death or hHF, contrary to expectations derived from preclinical animal models. Trial registration clinicaltrials.gov no. NCT00790205.

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 ± 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., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: Congestive heart failure (CHF) is commonly associated with nonvalvular atrial fibrillation (AF), and their combination may affect treatment strategies and outcomes., Objective: To assess the treatment strategies and 1-year clinical outcomes of antithrombotic and CHF therapies for patients with newly diagnosed AF with concomitant CHF stratified by etiology (ischemic cardiomyopathy [ICM] vs nonischemic cardiomyopathy [NICM])., Design, Setting, and Participants: The GARFIELD-AF registry is a prospective, noninterventional registry. A total of 52 014 patients with AF were enrolled between March 2010 and August 2016. A total of 11 738 patients 18 years and older with newly diagnosed AF (≤6 weeks' duration) and at least 1 investigator-determined stroke risk factor were included. Data were analyzed from December 2017 to September 2018., Exposures: One-year follow-up rates of death, stroke/systemic embolism, and major bleeding were assessed., Main Outcomes and Measures: Event rates per 100 person-years were estimated from the Poisson model and Cox hazard ratios (HRs) and 95% confidence intervals., Results: The median age of the population was 71.0 years, 22 987 of 52 013 were women (44.2%) and 31 958 of 52 014 were white (61.4%). Of 11 738 patients with CHF, 4717 (40.2%) had ICM and 7021 (59.8%) had NICM. Prescription of oral anticoagulant and antiplatelet drugs was not balanced between groups. Oral anticoagulants with or without antiplatelet drugs were used in 2753 patients with ICM (60.1%) and 5082 patients with NICM (73.7%). Antiplatelets were prescribed alone in 1576 patients with ICM (34.4%) and 1071 patients with NICM (15.5%). Compared with patients with NICM, use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (72.6% [3439] vs 60.3% [4236]) and of β blockers (63.3% [2988] vs 53.2% [3737]) was higher in patients with ICM. Rates of all-cause and cardiovascular death per 100 patient-years were significantly higher in the ICM group (all-cause death: ICM, 10.2; 95% CI, 9.2-11.1; NICM, 7.0; 95% CI, 6.4-7.6; cardiovascular death: ICM, 5.1; 95% CI, 4.5-5.9; NICM, 2.9; 95% CI, 2.5-3.4). Stroke/systemic embolism rates tended to be higher in ICM groups compared with NICM groups (ICM, 2.0; 95% CI, 1.6-2.5; NICM, 1.5; 95% CI, 1.3-1.9). Major bleeding rates were significantly higher in the ICM group (1.1; 95% CI, 0.8-1.4) compared with the NICM group (0.7; 95% CI, 0.5-0.9)., Conclusions and Relevance: Patients with ICM received oral anticoagulants with or without antiplatelet drugs less frequently and antiplatelets alone more frequently than patients with NICM, but they received angiotensin-converting enzyme inhibitors/angiotensin receptor blockers more often than patients with NICM. All-cause and cardiovascular death rates were higher in patients with ICM than patients with NICM., Trial Registration: ClinicalTrials.gov Identifier: NCT01090362.

Background: Peripheral blood metabolite profiles have yielded mechanistic insights into various cardiovascular disease states. We hypothesized that peripheral blood metabolite profiles would be associated with new onset atrial fibrillation (AF)., Methods and Results: The study population comprised 1892 patients without AF at baseline, who, as part the MURDOCK Cardiovascular Disease Study molecular profiling cohort (n = 2023), had previously had determination of levels of 69 metabolites from frozen, fasting plasma specimens obtained during coronary angiography. We used Cox proportional hazards models to examine the association of 13 uncorrelated metabolite factors created from these data using principal components analysis (PCA) with new occurrences of AF during a median follow up of 2.8 (0.1-4.9) years. A total of 233 patients developed new AF (12.3%) during follow up. Patients with new onset AF were older (median 67 vs. 60 years); more often white (82 vs. 71%) and male (68 vs. 60%), and had more comorbidities than those who did not develop AF. After adjustment, PCA factor 1 (medium chain acylcarnitines; hazard ratio [HR]: 1.11 [1.01-1.22]), factor 2 (short chain dicarboxylacylcarnitines; HR: 1.21 [1.09-1.34]) and factor 5 (long chain acylcarnitines; HR: 1.19 [1.06-1.34]) were associated with new onset AF., Conclusion: Metabolite profiles were associated with new onset AF among patients referred for coronary angiography. Validation of these observations in broader patient populations may provide better mechanistic insight into the development of AF, and may provide new opportunities for prevention and treatment., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Atrial fibrillation (AF) is an important preventable cause of stroke. Anticoagulation (AC) therapy can reduce this risk. However, prescribing patterns and outcomes in patients with non-valvular AF (NVAF) from Latin American countries are poorly described., Methods: Using data from the Global Anticoagulant Registry in the FIELD-AF (GARFIELD-AF), we examined the stroke prevention strategies and the 1-year outcomes in patients from four Latin American countries: Argentina, Brazil, Chile, and Mexico., Results: A total of 4162 patients (2010-2014) were included in this analysis. At the time of AF diagnosis, 39.9% of patients were prescribed vitamin K antagonists (VKA) ± antiplatelet (AP) therapy, 21.8% non-VKA oral anticoagulant (NOAC) ± AP, 24.1% AP only and 14.1% no antithrombotic treatment. The proportion of moderate-high risk patients receiving no AC therapy at participating centers was highest in Mexico (46.4%) and lowest in Chile (14.3%). During 1-year follow-up, the rates of all-cause mortality, stroke/SE and major bleeding were: 5.77 (95% CI) (5.06-6.56), 1.58 (1.23-2.02), and 0.99 (0.72-1.36) and per 100 person-years, respectively, which are higher than the global rates across all countries in GARFIELD-AF. Unadjusted rates of all-cause mortality were highest in Argentina, 6.95 (5.43-8.90), and lowest in Chile, 4.01 (2.92-5.52)., Conclusions: GARFIELD-AF results describes the marked variation in the baseline characteristics and patterns of antithrombotic treatments in patients with NVAF in four Latin American countries. Over one-third of patients with a moderate-to-high risk of stroke received no AC therapy, highlighting the need for improved management of patients according to national guideline. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362., (© 2019 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.)

Background: Modern cardiometabolic clinical trials often include cardiovascular death as a component of a composite primary outcome, requiring central adjudication by a clinical events committee to classify cause of death. However, sometimes the cause of death cannot be determined from available data. The US Food and Drug Administration has indicated that this circumstance should occur only rarely, but its prevalence has not been formally assessed., Methods: Data from 9 global clinical trials (2009-2017) with long-term follow-up and blinded, centrally adjudicated cause of death were used to calculate the proportion of deaths attributed to cardiovascular, noncardiovascular, or undetermined causes by therapeutic area (diabetes mellitus/pre-diabetes mellitus, stable atherosclerosis, atrial fibrillation, and acute coronary syndrome), region of patient enrollment, and year of trial manuscript publication. Patient- and trial-level variables associated with undetermined cause of death were identified using a logistic model., Results: Across 127 049 enrolled participants from 9 trials, there were 9259 centrally adjudicated deaths: 5012 (54.1%) attributable to cardiovascular causes, 2800 (30.2%) attributable to noncardiovascular causes, and 1447 (15.6%) attributable to undetermined causes. There was variability in the proportion of deaths ascribed to undetermined causes by trial therapeutic area, region of enrollment, and year of trial manuscript publication. On multivariable analysis, acute coronary syndrome or atrial fibrillation trial (versus atherosclerotic vascular disease or diabetes mellitus/pre-diabetes mellitus), longer time from enrollment to death, more recent trial manuscript publication year, enrollment in North America (versus Western Europe), female sex, and older age were associated with greater likelihood of death of undetermined cause., Conclusions: In 9 cardiometabolic clinical trials with long-term follow-up, approximately 16% of deaths had undetermined causes. This provides a baseline for quality assessment of clinical trials and informs operational efforts to potentially reduce the frequency of undetermined deaths in future clinical research.

Background: Atrial fibrillation is associated with increased risks of death, stroke/systemic embolism, and bleeding (incurred by antithrombotic therapy), which may occur early after diagnosis., Methods: We assessed the risk of early events (death, stroke/systemic embolism, and major bleeding) over 12 months and their relation to the time after diagnosis of atrial fibrillation in 52 014 patients prospectively enrolled in the GARFIELD-AF registry (Global Anticoagulant Registry in the FIELD-Atrial Fibrillation) between March 2010 and August 2016., Results: Over 12 months, 2140 patients died (mortality rate, 4.3; 95% CI, 4.2-4.5 per 100 person-years), of whom 288 (13.5%) died in the first month (6.8; 95% CI, 6.1-7.6). Over 12 months, 657 patients had a stroke/systemic embolism (1.3; 95% CI, 1.2-1.4) and 411 had a major bleeding (0.8; 95% CI, 0.8-0.9). During the first month, the rates (per 100 person-years) of stroke/systemic embolism and major bleed were 2.3 (95% CI, 1.9-2.8) and 1.5 (95% CI, 1.2-1.9), respectively. The elevated 1-month mortality rate was mostly attributable to cardiovascular mortality (3.5; 95% CI, 3.0-4.1), in particular, heart failure, sudden death, and acute coronary syndromes (1.0 [95% CI, 0.8-1.4], 0.6 [95% CI, 0.4-0.8], and 0.5 [95% CI, 0.3-0.8], respectively). Age, heart failure, prior stroke, history of cirrhosis, vascular disease, moderate-to-severe kidney disease, diabetes mellitus, and living in North or Latin America were independent predictors of a higher risk of early death, whereas anticoagulation and living in Europe or Asia were independent predictors of a lower risk of early death. A predictive model developed for the 1-month risk of death had a C-statistic of 0.81 (95% CI, 0.78-0.83)., Conclusions: The increased hazard of early events, in particular, cardiovascular mortality, in newly diagnosed atrial fibrillation points to the importance of comprehensive care for such patients and should alert clinicians to detect warning signs of possible early mortality., Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01090362.

Background:  Management of venous thromboembolism (VTE), encompassing both deep vein thrombosis (DVT) and pulmonary embolism (PE), varies worldwide., Methods:  The Global Anticoagulant Registry in the FIELD - Venous Thromboembolism (GARFIELD-VTE) is a prospective, observational study of 10,685 patients with objectively diagnosed VTE recruited from May 2014 to January 2017 at 417 sites in 28 countries. All patients are followed for at least 3 years. We describe the baseline characteristics of the study population and their management within 30 days of diagnosis., Results:  The median age was 60.2 years; 50.4% were male; 61.7% had DVT and 38.3% had PE ± DVT; and 32.3% were obese (body mass index ≥ 30 kg/m 2 ). The most common risk factors were surgery (12.5%), hospitalization (12.0%) and trauma to the lower limbs (7.8%). At the time of VTE diagnosis, 10.1% had active cancer and 5.7% were chronically immobilized. Treatment for VTE was anticoagulant (AC) therapy alone in 90.9% of patients; 5.1% received thrombolytic and/or surgical/mechanical therapy ± AC and 4.0% received no therapy. Pre-diagnosis, 12.8% received AC therapy alone and 0.2% received thrombolytic and/or surgical/mechanical therapy ± AC. After diagnosis, parenteral AC therapy alone was administered in 17.6% of patients, and it was followed by a direct oral AC (DOAC) in 16.4% or a vitamin K antagonist (VKA) in 26.8%. DOACs alone were prescribed to 32.3% of patients, while 5.9% received VKA alone., Conclusion:  The initial findings from this global registry highlight the heterogeneity in characteristics and management of VTE patients. Prospective follow-up will reveal the impact of this heterogeneity on outcomes., Competing Interests: Walter Ageno: Honoraria from Boehringer Ingelheim, Bayer Pharmaceuticals, BMS-Pfizer and Daiichi-Sankyo. Research support from Bayer Pharmaceuticals and Boehringer Ingelheim. Sylvia Haas: Honoraria from Aspen, Bayer Healthcare, BMS, Daiichi-Sankyo, Pfizer, Portola and Sanofi. Jeffrey I. Weitz: Honoraria from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Ionis, Janssen, Merck, Portola, Pfizer, Servier and Novartis. Samuel Z. Goldhaber: Grants from BiO2 Medical, Boehringer Ingelheim, Bristol Meyers Squibb, BTG EKOS, Daiichi-Sankyo, National Heart Lung and Blood Institute of the National Institutes of Health, Janssen and the Thrombosis Research Group. Personal fees (all consultancy less than $10K) from Bayer, Boehringer Ingelheim, Bristol Meyers Squibb, Daiichi-Sankyo, Janssen, Portola and Zafgen. Alexander G. G. Turpie: Personal fees from Bayer Pharma AG and Janssen. Shinya Goto: Honoraria from Sanofi, AstraZeneca and Bayer. Research funding from Sanofi. Sebastian Schellong: Speaker fees from Bayer Healthcare, Boehringer Ingelheim, Bristol Meyer Squibb, Daiichi-Sankyo, Sanofi Aventis and Pfizer. Consultancy fees from Bayer Healthcare, Boehringer Ingelheim, Daiichi-Sankyo, Sanofi Aventis and Pfizer. Joern Dalsgaard Nielsen: Honoraria from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Leo Pharma and Pfizer. Henri Bounameaux: Research grant, speaker's fees and honoraria for studies with rivaroxaban from Bayer Healthcare. Honoraria from Sanofi. Lorenzo Mantovani: Grants and personal fees from Bayer Healthcare, Boehringer Ingelheim, Pfizer and Daiichi-Sankyo. Paolo Prandoni: Personal fees from Bayer Pharma, Pfizer, Daiichi-Sankyo, Sanofi and Rovi Pharmaceuticos. Professor Ajay K. Kakkar is a principal investigator and received research Grants from Bayer Healthcare; he received personal fee from Bayer Healthcare, Boehringer Ingelheim Pharma, Daiichi-Sankyo Europe, Sanofi SA and Janssen Pharma. Pantep Angchaisuksiri, Karen Pieper and Gloria Kayani declare that they have no conflicts of interest in the research., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective non-interventional study of stroke prevention in patients with newly diagnosed non-valvular AF (NAVF) that is being conducted in 35 countries. Methods and Results: A total of 52,081 patients with a new diagnosis of NVAF were enrolled prospectively in GARFIELD-AF. Of these, 4859 (9.3%) were recruited in Japan (2010-2016). In cohort 1 (2010-2011), few patients were on non-vitamin K antagonist oral anticoagulants (NOAC) globally. From cohort 2 onwards (2011-2016), however, there was a rapid increase in NOAC use around the globe, especially in Japan. By the last year of enrolment (2015-2016), 67.9% of patients in Japan and 43.1% of patients globally were on NOAC±antiplatelet therapy (AP). In Japan and globally, 17.0% and 12.2% of patients, respectively, did not receive stroke prevention treatment. Few patients in Japan (5.7%) received AP only. Compared with the other countries, the unadjusted rates of all-cause mortality and major bleeding were low, while rates of stroke/systemic embolism were similar after 1 year of follow-up., Conclusions: GARFIELD-AF continues to provide important information on the homogeneity and heterogeneity of baseline characteristics and treatment patterns in patients with newly diagnosed NVAF. This diversity reflects the differences in outcomes in Japan compared with the rest of the world.

Importance: Black and Hispanic patients are less likely than white patients to use oral anticoagulants for atrial fibrillation. Little is known about racial/ethnic differences in use of direct-acting oral anticoagulants (DOACs) for atrial fibrillation., Objective: To assess racial/ethnic differences in the use of oral anticoagulants, particularly DOACs, in patients with atrial fibrillation., Design, Setting, and Participants: This cohort study used data from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II, a prospective, US-based registry of outpatients with nontransient atrial fibrillation 21 years and older who were followed up from February 2013 to July 2016. Data were analyzed from February 2017 to February 2018., Exposures: Self-reported race/ethnicity as white, black, or Hispanic., Main Outcomes and Measures: The primary outcome was use of any oral anticoagulant, particularly DOACs. Secondary outcomes included the quality of anticoagulation received and oral anticoagulant discontinuation at 1 year., Results: Of 12 417 patients, 11 100 were white individuals (88.6%), 646 were black individuals (5.2%), and 671 were Hispanic individuals (5.4%) with atrial fibrillation. After adjusting for clinical features, black individuals were less likely to receive any oral anticoagulant than white individuals (adjusted odds ratio [aOR], 0.75 [95% CI, 0.56, 0.99]) and less likely to receive DOACs if an anticoagulant was prescribed (aOR, 0.63 [95% CI, 0.49-0.83]). After further controlling for socioeconomic factors, oral anticoagulant use was no longer significantly different in black individuals (aOR, 0.78 [95% CI, 0.59-1.04]); among patients using oral anticoagulants, DOAC use remained significantly lower in black individuals (aOR, 0.73 [95% CI, 0.55-0.95]). There was no significant difference between white and Hispanic groups in use of oral anticoagulants. Among patients receiving warfarin, the median time in therapeutic range was lower in black individuals (57.1% [IQR, 39.9%-72.5%]) and Hispanic individuals (51.7% [interquartile range {IQR}, 39.1%-66.7%]) than white individuals (67.1% [IQR, 51.8%-80.6%]; P < .001). Black and Hispanic individuals treated with DOACs were more likely to receive inappropriate dosing than white individuals (black patients, 61 of 394 [15.5%]; Hispanic patients, 74 of 409 [18.1%]; white patients, 1003 of 7988 [12.6%]; P = .01). One-year persistence on oral anticoagulants was the same across groups., Conclusions and Relevance: After controlling for clinical and socioeconomic factors, black individuals were less likely than white individuals to receive DOACs for atrial fibrillation, with no difference between white and Hispanic groups. When atrial fibrillation was treated, the quality of anticoagulant use was lower in black and Hispanic individuals. Identifying modifiable causes of these disparities could improve the quality of care in atrial fibrillation.

Asymptomatic atrial fibrillation (AF) is being increasingly diagnosed via implantable devices, screening, and inpatient telemetry. Management of asymptomatic AF is controversial, in part, because the associated risks have not been well described. We examined the incidence of major adverse outcomes in patients with asymptomatic versus symptomatic AF using Outcomes Registry for Better Informed Treatment of Atrial, a nationwide US registry of AF patients. We compared stroke and/or non-central nervous system (CNS) embolism, major adverse cardiovascular and neurologic events, bleeding, and death in 9,319 asymptomatic (defined by European Heart Rhythm Association score = 1 or "no symptoms") versus symptomatic patients. Overall, median (interquartile) age was 75 (67 to 82) years, 3,944 (42%) were women, and 38% versus 37% were asymptomatic based on physician versus patient-reported symptoms. Compared with those with symptoms, physician-defined asymptomatic patients were less likely to be woman (35%/47%) or be on an antiarrhythmic agent (22%/33%), but were more likely to have permanent and/or persistent AF (51%/40%). CHA 2 DS 2 -VASc scores did not vary by symptom status. After adjustment, risk of first stroke and/or non-CNS embolism (hazard ratio [HR] 0.85 [95% confidence interval {CI} 0.63 to 1.16], p = 0.32), major adverse cardiovascular and neurologic events (HR 0.88 [95% CI 0.76 to 1.03], p = 0.11), bleeding (HR 0.85 [95% CI 0.72 to 1.00], p = 0.05), and death (HR 0.99 [95% CI 0.87 to 1.13], p = 0.88) were similar in asymptomatic (European Heart Rhythm Association = 1) and symptomatic AF, respectively. Prospective, randomized studies are needed to further define associated adverse events and delineate optimal prophylactic therapies in patients with asymptomatic AF., (Copyright © 2018. Published by Elsevier Inc.)

Background: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry., Methods and Results: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up., Conclusion: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362., (Copyright © 2018 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.)

Background: Although bradyarrhythmias have been observed with ticagrelor and its use with advanced atrioventricular block is not recommended, questions arise regarding its use in patients with mild conduction abnormalities. The objectives were to compare rates of clinically relevant arrhythmias in relation to any mild baseline conduction abnormality in patients with acute coronary syndrome randomized to ticagrelor versus clopidogrel., Methods: We included all subjects in the electrocardiographic (ECG) substudy of the Platelet Inhibition and Patient Outcomes trial, excluding those with missing baseline ECG or with a pacemaker at baseline (N = 15,460). Conduction abnormality was defined as sinus bradycardia, first-degree atrioventricular block, hemiblock, or bundle-branch block. The primary arrhythmic outcome was the composite of any symptomatic brady- or tachyarrhythmia, permanent pacemaker placement, or cardiac arrest through 12 months., Results: Patients with baseline conduction abnormalities (n = 4,256, 27.5%) were older and more likely to experience the primary arrhythmic outcome. There were no differences by ticagrelor versus clopidogrel in the composite arrhythmic end point in those with baseline conduction disease (1-year cumulative incidence rate: 17% for both study arms; hazard ratio: 0.99 [0.86-1.15]) or without baseline conduction disease (1-year cumulative incidence rate: clopidogrel 12.8% vs ticagrelor 12.4%; hazard ratio: 0.98 (0.88-1.09). There were also no statistically significant differences between ticagrelor and clopidogrel in the rates of bradycardic (or any individual arrhythmic) events in patients with baseline conduction abnormalities., Conclusions: Ticagrelor compared to clopidogrel did not increase arrhythmic events even in subjects with acute coronary syndrome who present with mild conduction abnormalities on their baseline ECG., (Copyright © 2018. Published by Elsevier Inc.)

Background: Length of stay after non-ST-segment elevation myocardial infarction (NSTEMI) continues to decrease, but information to guide duration of hospitalization is limited., Methods: We used landmark analyses, in which the landmark defined potential days of discharge, to estimate complication rates on the first day the patient would have been out of the hospital, and estimated associations between timing of discharge and 30-day and 1-year event-free survival after discharge among NSTEMI patients., Results: Among 20,410 NSTEMI patients, median length of stay was 7 (4, 12) days; 3,209 (15.7%) experienced a cardiac complication on days 0 to 2 and 1,322 (6.5%) were discharged without complications during hospital days 0 to 2. At the start of day 3, 15,879 patients (77.8%) were still hospitalized without complications. Of these, 1,689 (10.6%) were discharged event-free on day 3. Adjusted event-free survival rates of death or myocardial infarction from day 4 to 30 days after among the 1,689 patients was 99.1% compared with 93.1% for the 14,190 who remained hospitalized at the end of day 3. For 1-year mortality, these rates were 98.1% and 96.4%, respectively. Among 13,334 patients hospitalized without complications at the start of day 4, 1,706 were discharged event-free that day. Adjusted survival rates among these patients, compared with those still hospitalized at the end of day 4, were 98.0% versus 93.7% for 30-day death or myocardial infarction and 97.8% versus 96.1% for 1-year mortality., Conclusions: Patients with NSTEMI who had no serious complications during the first 2 hospital days were at low risk of subsequent short- and intermediate-term death or ischemic events., (Copyright © 2018. Published by Elsevier Inc.)

Background: Intensive care unit (ICU) use for initially stable patients presenting with non-ST-segment-elevation myocardial infarction (NSTEMI) varies widely across hospitals and minimally correlates with severity of illness. We aimed to develop a bedside risk score to assist in identifying high-risk patients with NSTEMI for ICU admission., Methods and Results: Using the Acute Coronary Treatment and Intervention Outcomes Network (ACTION) Registry linked to Medicare data, we identified patients with NSTEMI aged ≥65 years without cardiogenic shock or cardiac arrest on presentation. Complications requiring ICU care were defined as subsequent development of cardiac arrest, shock, high-grade atrioventricular block, respiratory failure, stroke, or death during the index hospitalization. We developed and validated a model and integer risk score (Acute Coronary Treatment and Intervention Outcomes Network (ACTION) ICU risk score) that uses variables present at hospital admission to predict requirement for ICU care. Of 29 973 patients with NSTEMI, 4282 (14%) developed a complication requiring ICU-level care, yet 12 879 (43%) received care in an ICU. Signs or symptoms of heart failure, initial heart rate, initial systolic blood pressure, initial troponin, initial serum creatinine, prior revascularization, chronic lung disease, ST-segment depression, and age had statistically significant associations with requirement for ICU care after adjusting for other risk factors. The ACTION ICU risk score had a C-statistic of 0.72. It identified 11% of patients as having very high risk (>30%) of developing complications requiring ICU care and 49% as having low likelihood (<10%) of requiring an ICU., Conclusions: The ACTION ICU risk score quantifies the risk of initially stable patients with NSTEMI developing a complication requiring ICU care, and could be used to more effectively allocate limited ICU resources., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background and Purpose: Patients with prior stroke are at greater risk for recurrent cardiovascular events post-acute coronary syndromes (ACS) and may have a different risk/benefit profile with antithrombotic therapy than patients without prior stroke., Methods: We studied 7391 patients with ACS from APPRAISE-2, stratified by the presence or absence of prior stroke. Baseline characteristics and outcomes of cardiovascular death, myocardial infarction (MI), or stroke were compared between groups. Interactions between prior stroke, treatment assignment (apixaban vs placebo), and outcomes were tested before and after multivariable adjustment with Cox proportional hazards models., Results: A total of 902 patients (12%) had prior stroke. Those with prior stroke were older (69 vs 67 years), had more hypertension (91% vs 77%), peripheral vascular disease (22% vs18%), and impaired renal function (38% vs 30%) but less diabetes (44% vs 48%) than those without prior stroke. Patients with prior stroke vs no prior stroke had higher unadjusted rates of cardiovascular death (4.8% vs 4.0%), MI (11.2% vs 7.1%), and ischemic stroke (3.2% vs 0.9%). Patients with prior stroke assigned to apixaban had similar rates of the composite of cardiovascular death, MI, or stroke compared with those assigned to placebo (HR 1.39; 95% CI 0.92-2.08). Patients without prior stroke assigned to apixaban had similar rates of cardiovascular death, MI, or ischemic stroke compared with those assigned to placebo (HR 0.87; 95% CI 0.73-1.04; P-interaction=.041). Median follow-up was 240 days., Conclusions: Patients with prior stroke are at higher risk for recurrent cardiovascular events post-ACS and had a differential risk/benefit profile with oral anticoagulation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

Aims: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result., Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0 and 18 months (such that the total time of follow-up was 24 months; data collection December 2009 and October 2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between March 2010 and October 2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs. 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51-3.67] vs. 4.05 [95% CI 3.53-4.63]; P = 0.016)., Conclusion: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment., Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier for GARFIELD-AF (NCT01090362)., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions please email: journals.permissions@oup.com.)

Objectives: To provide an accurate, web-based tool for stratifying patients with atrial fibrillation to facilitate decisions on the potential benefits/risks of anticoagulation, based on mortality, stroke and bleeding risks., Design: The new tool was developed, using stepwise regression, for all and then applied to lower risk patients. C-statistics were compared with CHA 2 DS 2 -VASc using 30-fold cross-validation to control for overfitting. External validation was undertaken in an independent dataset, Outcome Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF)., Participants: Data from 39 898 patients enrolled in the prospective GARFIELD-AF registry provided the basis for deriving and validating an integrated risk tool to predict stroke risk, mortality and bleeding risk., Results: The discriminatory value of the GARFIELD-AF risk model was superior to CHA 2 DS 2 -VASc for patients with or without anticoagulation. C-statistics (95% CI) for all-cause mortality, ischaemic stroke/systemic embolism and haemorrhagic stroke/major bleeding (treated patients) were: 0.77 (0.76 to 0.78), 0.69 (0.67 to 0.71) and 0.66 (0.62 to 0.69), respectively, for the GARFIELD-AF risk models, and 0.66 (0.64-0.67), 0.64 (0.61-0.66) and 0.64 (0.61-0.68), respectively, for CHA 2 DS 2 -VASc (or HAS-BLED for bleeding). In very low to low risk patients (CHA 2 DS 2 -VASc 0 or 1 (men) and 1 or 2 (women)), the CHA 2 DS 2 -VASc and HAS-BLED (for bleeding) scores offered weak discriminatory value for mortality, stroke/systemic embolism and major bleeding. C-statistics for the GARFIELD-AF risk tool were 0.69 (0.64 to 0.75), 0.65 (0.56 to 0.73) and 0.60 (0.47 to 0.73) for each end point, respectively, versus 0.50 (0.45 to 0.55), 0.59 (0.50 to 0.67) and 0.55 (0.53 to 0.56) for CHA 2 DS 2 -VASc (or HAS-BLED for bleeding). Upon validation in the ORBIT-AF population, C-statistics showed that the GARFIELD-AF risk tool was effective for predicting 1-year all-cause mortality using the full and simplified model for all-cause mortality: C-statistics 0.75 (0.73 to 0.77) and 0.75 (0.73 to 0.77), respectively, and for predicting for any stroke or systemic embolism over 1 year, C-statistics 0.68 (0.62 to 0.74)., Conclusions: Performance of the GARFIELD-AF risk tool was superior to CHA 2 DS 2 -VASc in predicting stroke and mortality and superior to HAS-BLED for bleeding, overall and in lower risk patients. The GARFIELD-AF tool has the potential for incorporation in routine electronic systems, and for the first time, permits simultaneous evaluation of ischaemic stroke, mortality and bleeding risks., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier for GARFIELD-AF (NCT01090362) and for ORBIT-AF (NCT01165710)., Competing Interests: Competing interests: KAAF reports grants and personal fees from Bayer, and Johnson and Johnson, personal fees from Lilly, grants and personal fees from AstraZeneca and personal fees from Sanofi/Regeneron outside the submitted work. JEL and KSP have provided statistical support and thought leadership for the Thrombosis Research Institute, during the conduct of the study, and KSP has received personal fees from Bayer outside the submitted work. J-PB reports personal fees from Aspen outside the submitted work. AJC is an advisor to Bayer, Boehringer Ingelheim, Pfizer/BMS and Daiichi Sankyo. DAF reports personal fees from Bayer outside the submitted work. SZG reports grants from BiO2 Medical, Boehringer-Ingelheim, Bristol Meyers Squibb, BTG EKOS, Daiichi Sankyo, National Heart Lung and Blood Institute of the National Institutes of Health, Janssen and Thrombosis Research Group and personal fees from Bayer, Boehringer-Ingelheim, Bristol Meyers Squibb, Daiichi Sankyo, Janssen and Portola outside the submitted work. SG reports personal fees from Bayer, grants from Sanofi, grants from Pfizer, personal fees from Daiichi-Sankyo, personal fees from AstraZeneca during the conduct of the study and grants from Bayer outside the submitted work. SH reports personal fees from Aspen, Bayer AG, BMS, Daiichi-Sankyo, Pfizer and Sanofi outside the submitted work. WH reports personal fees from Bayer during the conduct of the study. GK reports grants from Bayer during the conduct of the study. LGM reports grants and personal fees from Bayer AG during the conduct of the study, and grants from Boehringer Ingelheim, grants and personal fees from Pfizer and personal fees from Daiichi Sankyo outside the submitted work. FM reports grants and other from Bayer AG during the conduct of the study, and other from Bayer AG outside the submitted work. FM is an employee of Bayer AG. JP has nothing to disclose. AGGT reports consultant fees from Bayer AG during the conduct of the study. FWAV reports personal fees from Boehringer-Ingelheim, Bayer AG, BMS/Pfizer and Daiichi-Sankyo during the conduct of the study and personal fees from AstraZeneca outside the submitted work. AKK reports grants and personal fees from Bayer AG, Boehringer-Ingelheim Pharma, Daiichi Sankyo Europe, Sanofi SA and Janssen Pharma outside the submitted work., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Intensive risk factor modification significantly improves outcomes for patients with diabetes mellitus and cardiovascular disease. However, the degree to which secondary prevention treatment goals are achieved in international clinical practice is unknown., Methods: Attainment of 5 secondary prevention parameters-aspirin use, lipid control (low-density lipoprotein cholesterol <70 mg/dL or statin therapy), blood pressure control (<140 mm Hg systolic, <90 mm Hg diastolic), angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use, and nonsmoking status-was evaluated among 13 616 patients from 38 countries with diabetes mellitus and known cardiovascular disease at entry into TECOS (Trial Evaluating Cardiovascular Outcomes With Sitagliptin). Logistic regression was used to evaluate the association between individual and regional factors and secondary prevention achievement at baseline. Cox proportional hazards regression analysis was used to determine the association between baseline secondary prevention achievement and cardiovascular death, myocardial infarction, or stroke., Results: Overall, 29.9% of patients with diabetes mellitus and cardiovascular disease achieved all 5 secondary prevention parameters at baseline, although 71.8% achieved at least 4 parameters. North America had the highest proportion (41.2%), whereas Western Europe, Eastern Europe, and Latin America had proportions of ≈25%. Individually, blood pressure control (57.9%) had the lowest overall attainment, whereas nonsmoking status had the highest (89%). Over a median 3.0 years of follow-up, a higher baseline secondary prevention score was associated with improved outcomes in a step-wise graded relationship (adjusted hazard ratio, 0.60; 95% confidence interval, 0.47-0.77 for those patients achieving all 5 measures versus those achieving ≤2)., Conclusions: In an international trial population, significant opportunities exist to improve the quality of cardiovascular secondary prevention care among patients with diabetes mellitus and cardiovascular disease, which in turn could lead to reduced risk of downstream cardiovascular events., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00790205., (© 2017 American Heart Association, Inc.)

Background: Most studies of risk assessment or stratification in patients with myocardial infarction (MI) have been static and fail to account for the evolving nature of clinical events and care processes. We sought to identify predictors of mortality, cardiovascular death or nonfatal MI, and cardiovascular death or nonfatal heart failure (HF) over time in patients with HF, left ventricular systolic dysfunction, or both post-MI., Methods and Results: Using data from the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial, we developed models to estimate the association between patient characteristics and the likelihood of experiencing an event from the time of a follow-up visit until the next visit. The intervals are: hospital arrival to discharge or 14 days, whichever occurs first; hospital discharge to 30 days; 30 days to 6 months; and 6 months to 3 years. Models were also developed to predict the entire 3-year follow-up period using baseline information. Multivariable Cox proportional hazards modeling was used throughout with Wald chi-squares as the comparator of strength for each predictor. For the baseline model of overall mortality, the 3 strongest predictors were age (adjusted hazard ratio [HR], 1.35; 95% CI, 1.28-1.42; P<0.0001), baseline heart rate (adjusted HR, 1.17; 95% CI, 1.14-1.21; P<0.0001), and creatinine clearance (≤100 mL/min; adjusted HR, 0.86; 95% CI, 0.84-0.89; P<0.0001). According to the integrated discrimination improvement (IDI) and net reclassification improvement (NRI) indices, the updated model had significant improvement over the model with baseline covariates only in all follow-up periods and with all outcomes., Conclusions: Patient information assessed closest to the time of the outcome was more valuable in predicting death when compared with information obtained at the time of the index hospitalization. Using updated patient information improves prognosis over using only the information available at the time of the index event., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Red blood cell distribution width (RDW) strongly predicts clinical outcomes among patients with coronary disease and heart failure. The factors underpinning this association are unknown., Methods: In 6,447 individuals enrolled in the Measurement to Understand the Reclassification of Disease of Cabarrus/Kannapolis (MURDOCK) Study who had undergone coronary angiography between 2001 and 2007, we used Cox proportional hazards modeling to examine the adjusted association between RDW and death, and death or myocardial infarction (MI). Multiple linear regression using the R(2) model selection method was then used to identify clinical factors associated with variation in RDW., Results: Median follow-up was 4.2 (interquartile range 2.3-5.9) years, and the median RDW was 13.5% (interquartile range 12.9%-14.3%, clinical laboratory reference range 11.5%-14.5%). Red blood cell distribution width was independently associated with death (adjusted hazard ratio 1.13 per 1% increase in RDW, 95% CI 1.09-1.17), and death or MI (adjusted hazard ratio 1.12, 95% CI 1.08-1.16). Twenty-seven clinical characteristics and laboratory measures were assessed in the multivariable linear regression model; a final model containing 18 variables explained only 21% of the variation in RDW., Conclusions: Although strongly associated with death and death or MI, only one-fifth of the variation in RDW was explained by routinely assessed clinical characteristics and laboratory measures. Understanding the latent factors that explain variation in RDW may provide insight into its strong association with risk and identify novel targets to mitigate that risk., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Adverse event collection in randomized clinical trials establishes drug safety. Although costly and regulated, it is rarely studied., Methods: Adverse event data from 4 clinical trials (APPRAISE-2, PLATO, TRACER, TRILOGY ACS) comprising 48,118 participants with acute coronary syndromes were pooled to compare patterns and determinants of reporting. Events were classified as serious (SAE) or nonserious (AE) from hospital discharge to 1 year; study end points were excluded., Results: In total, 84,901 events were reported. Of those, 12,266 (14.4%) were SAEs and 72,635 (85.6%) were AEs. Of all participants, 7,823 (16.3%) had SAEs, 18,124 (37.7%) had only AEs, and 22,171 (46.1%) had neither. Nonserious adverse events were distributed across system organ classes: general disorders (11%), infection (10%), gastrointestinal (10%), respiratory (9%), cardiovascular (8.4%), and other (35%). Serious adverse events had a higher proportion of cardiovascular causes (14.0%). Event reporting was highest after hospital discharge, decreasing rapidly during the following 3 months. In a Cox proportional hazards model, chronic obstructive pulmonary disease (hazard ratio 1.58, 95% CI 1.44-1.74), heart failure (1.55, 1.40-1.70), older age, and female sex were independent predictors of more SAEs, whereas enrollment in Eastern Europe (0.63, 0.58-0.69) or Asia (0.84, 0.75-0.94) were independent predictors of fewer SAEs., Conclusions: Half of all participants reported adverse events in the year after acute coronary syndrome; most were AEs and occurred within 3 months. The high volume of events, as well as the variation in SAE reporting by characteristics and enrollment region, indicates that efforts to refine event collection in large trials are warranted., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions., Methods and Results: In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS2 score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P<0.0001) and age ≥75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P<0.0001) were associated with higher all-cause mortality. Multiple additional characteristics were independently associated with higher mortality, with decreasing creatinine clearance, chronic obstructive pulmonary disease, male sex, peripheral vascular disease, and diabetes being among the most strongly associated (model C-index 0.677)., Conclusions: In a large population of patients anticoagulated for nonvalvular atrial fibrillation, ≈7 in 10 deaths were cardiovascular, whereas <1 in 10 deaths were caused by nonhemorrhagic stroke or systemic embolism. Optimal prevention and treatment of heart failure, renal impairment, chronic obstructive pulmonary disease, and diabetes may improve survival., Clinical Trial Registration: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00403767., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Among patients presenting with ST-segment elevation myocardial infarction (STEMI) for primary percutaneous coronary intervention (PCI), the associations between clinical outcomes and both baseline renal function and the development of acute kidney injury (AKI) have not been reported in a trial population with unselected baseline renal function., Methods: Patients enrolled in the APEX-AMI trial who underwent primary PCI for the treatment of STEMI were categorized according to (a) baseline renal function and (b) the development of AKI. Patient characteristics, clinical outcomes, and treatment patterns were analyzed according to baseline renal function and the development of AKI. A prediction model for AKI after primary PCI for STEMI was also developed., Results: A total of 5,244 patients were included in this analysis and stratified according to baseline estimated glomerular filtration rate (eGFR) (milliliters per minute per 1.73 m(2)) of >90, 60 to 90, 30 to 59, or <30 or as dialysis dependent. Patients with lower eGFR were older, more often female, and less often treated with evidence-based medicines and had worse angiographic outcomes and higher mortality. The rates of AKI for patients with a baseline eGFR of >90, 60 to 90, 30 to 59, and <30 were 2.5%, 4.1%, 8.1%, and 1.6%, respectively (P < .0001). The strongest predictors of AKI were age and presenting in Killip class III or IV., Conclusions: Among patients undergoing primary PCI for STEMI, impaired renal function at presentation and development of post-PCI AKI were highly associated with worse clinical and angiographic outcomes, including death. The risk of developing AKI was low and only modestly associated with baseline renal function., (Copyright © 2015 Elsevier Inc. All rights reserved.)