Antithrombotic Therapy for Atrial Fibrillation CHEST Guideline and Expert Panel Report Gregory Y. H. Lip, MD; Amitava Banerjee, MD, DPhil; Giuseppe Boriani, MD, PhD; Chern en Chiang, MD, PhD; Ramiz Fargo, MD, FCCP; Ben Freedman, MD, PhD; Deirdre A. Lane, PhD; Christian T. Ruff, MD, MPH; Mintu Turakhia, MD; David Werring, PhD; Sheena Patel, MPH; and Lisa Moores, MD, FCCP BACKGROUND: The risk of stroke is heterogeneous across different groups of patients with atrial brillation (AF), being dependent on the presence of various stroke risk factors. We provide recommendations for antithrombotic treatment based on net clinical bene t for patients with AF at varying levels of stroke risk and in a number of common clinical scenarios. METHODS: Systematic literature reviews were conducted to identify relevant articles published from the last formal search perfomed for the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th Edition). The overall quality of the evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. Graded recommendations and ungraded consensus-based statements were drafted, voted on, and revised until consensus was reached. RESULTS: For patients with AF without valvular heart disease, including those with paroxysmal AF, who are at low risk of stroke (eg, CHA2DS2-VASc [congestive heart failure, hypertension, age $ 75 (doubled), diabetes, stroke (doubled)-vascular disease, age 65-74 and sex category ABBREVIATIONS: ABC = Atrial brillation Better Care; ACS = acute coronary syndrome; ACTIVE W = Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events; ACUTE = Assessment of Cardioversion Using Transesophageal Echocardiog- raphy; AFFIRM = Atrial Fibrillation Follow-up Investigation of Sinus Rhythm Management; AHRE = atrial high-rate episode; aPTT = activated partial thromboplastin time; ARISTOTLE = Apixaban for Reduction of Stroke and Other Thromboembolic Events in Atrial Fibrillation; ATRIA = Anticoagulation and Risk Factors in Atrial Fibrillation; AVERROES = Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment; BRIDGE = Bridging Anticoagulation in Patients who Require Tem- porary Interruption of Warfarin Therapy for an Elective Invasive Procedure or Surgery; CAA = cerebral amyloid angiopathy; CHA2DS2-VASc = congestive heart failure, hypertension, age $75 (doubled), diabetes, stroke (doubled)-vascular disease, age 65-74 and sex category (female); CHADS2 = congestive heart failure; hyper- tension = age; diabetes = stroke (doubled); CIED = cardiac implanted electrical device; CKD = chronic kidney disease; CMB = cerebral microbleed; COI = con icts of interest; CrCl = creatinine clearance; DAPT = dual antiplatelet therapy; ESUS = embolic stroke of unde- termined source; GRADE = Grading of Recommendations, Assess- ment, Development, and Evaluation; HAS-BLED = hypertension, abnormal renal/liver function (1 point each), stroke, bleeding history or predisposition, labile INR, elderly (0.65), drugs/alcohol concom- itantly (1 point each); HEMORR2HAGES = hepatic or renal disease, ethanol abuse, malignancy, older, reduced platelet count/function, hypertension, anemia, genetic factors, excessive fall risk, and stroke; HF = heart failure; HR = hazard ratio; ICH = intracranial hemor- rhage; INR = international normalized ratio; LAA = left atrial appendage; LAAO = left atrial appendage occlusion; LMWH = low- molecular-weight heparin; MI = myocardial infarction; MOST = Atrial Diagnostics Ancillary Study of the Mode Selection Trial; NOAC = non-vitamin K antagonist oral anticoagulant drug; OAC = oral anticoagulant; o.d. = omni die (every day); PAD = peripheral arterial disease; PCC = prothrombin complex concentrate; PCI = percutaneous coronary intervention; PREVAIL = Prospective Ran- domized Evaluation of the Watchman LAA Closure Device In Pa- tients With Atrial Fibrillation Versus Long Term Warfarin Therapy trial; PROTECT AF = Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation; RCT = ran- domized controlled trial; RE-ALIGN = Randomized, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients after Heart Valve Replacement; RE-LY = Ran- domized Evaluation of Long-term Anticoagulant Therapy with Dabigatran Etexilate; RE-VERSE AD = Reversal Effects of Idar- ucizumab on Active Dabigatran; ROCKET AF = Rivaroxaban Once daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; RR = risk ratio; SPAF-I = Stroke Prevention in AF; TEE = transesophageal echocardiography; TIA = transient ischemic attack; t.i.d. = ter in die (three times daily); TT = thrombin time; TTE = transthoracic echocardiography; TTR = time in therapeutic range; UFH = unfractionated heparin; VKA = vitamin K antagonist AFFILIATIONS: From the Institute of Cardiovascular Sciences, Uni- versity of Birmingham, United Kingdom; Liverpool Centre for Car- diovascular Science, University of Liverpool, and Liverpool Heart and Chest Hospital, Liverpool, United Kingdom; and Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark (Dr Lip); Institute of Health Informatics, [ Evidence-Based Medicine ] (female)] score of 0 in males or 1 in females), we suggest no antithrombotic therapy. The next step is to consider stroke prevention (ie, oral anticoagulation therapy) for patients with 1 or more non-sex CHA2DS2-VASc stroke risk factors. For patients with a single non-sex CHA2DS2-VASc stroke risk factor, we suggest oral anticoagulation rather than no therapy, aspirin,orcombinationtherapywithaspirinandclopidogrel;andforthoseathighriskofstroke(eg, CHA2DS2-VASc $ 2 in males or $ 3 in females), we recommend oral anticoagulation rather than notherapy,aspirin,orcombinationtherapywithaspirinandclopidogrel.Wherewerecommendor suggest in favor of oral anticoagulation, we suggest using a non-vitamin K antagonist oral anti- coagulant drug rather than adjusted-dose vitamin K antagonist therapy. With the latter, it is important to aim for good quality anticoagulation control with a time in therapeutic range > 70%. Attention to modi able bleeding risk factors (eg, uncontrolled BP, labile international normalized ratios, concomitant use of aspirin or nonsteroidal antiin ammatory drugs in an anticoagulated patient, alcohol excess) should be made at each patient contact, and HAS-BLED (hypertension, abnormal renal/liver function [1 point each], stroke, bleeding history or predisposition, labile in- ternationalnormalized ratio, elderly (0.65), drugs/alcoholconcomitantly [1 point each]) score used to assess the risk of bleeding where high risk patients ($ 3) should be reviewed and followed up more frequently. CONCLUSIONS: Oral anticoagulation is the optimal choice of antithrombotic therapy for patients with AF with $1 non-sex CHA2DS2-VASc stroke risk factor(s). KEY WORDS: antithrombotic therapy; atrial brillation; evidence-based medicine; guidelines Note on Shaded Text: In this guideline, shaded text with an asterisk (shading appears in PDF le only) refers to recommendations that remain unchanged from the previous version of the guideline. Summary of Recommendations 1. For patients with AF, including those with paroxysmal AF, stroke risk should be assessed using a risk factor based approach, rather than an categorization into low, moderate/high risk strata. We recommend use of the CHA2DS2-VASc as a simple clinical based stroke risk score to initially identify low stroke risk patients who should not be offered antithrombotic therapy to prevent stroke and reduce mortality (Strong recommendation, moderate quality evidence). Remark: Low risk patients are generally those age < 65 and lone AF irrespective of sex (this includes those with a CHA2DS2-VASc score 0 in males, or 1 in females). 2. Subsequent to this initial step, for patients with AF, including those with paroxysmal AF, we recommend stroke prevention should be offered to those AF University College London (Dr Banerjee), London, United Kingdom; Cardiology Division, Department of Biomedical, Metabolic and Neural Sciences, University of Modena & Reggio Emilia, Modena University Hospital (Dr Boriani), Modena, Italy; General Clinical Research Center and Division of Cardiology, Taipei Veterans General Hospital and National Yang-Ming University (Dr Chiang), Taipei, Taiwan; Division of Pulmonary and Critical Care, Department of Internal Medicine, Riverside University Medical Center, Moreno Valley, CA, and Division of Pulmonary, Critical Care, Hyperbaric, and Sleep Medicine, Department of Internal Medicine, Loma Linda University Medical Center (Dr Fargo), Loma Linda, CA; Heart Research Institute/Charles Perkins Centre, University of Sydney and Department of Cardiology Concord Hospital, University of Sydney (Dr Freedman), Sydney, Australia; Institute of Cardiovascular Sciences, University of Bir- mingham, United Kingdom, and Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Faculty of Health, Aalborg Univer- sity (Dr Lane), Aalborg, Denmark; Cardiovascular Medicine Division, Brigham and Women s Hospital, Harvard Medical School (Dr Ruff), Boston, MA; Department of Medicine, Stanford University School of Medicine (Dr Turakhia), Stanford, CA; Stroke Research Centre, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, University College Hospitals NHS Foundation Trust (Dr Werring), London, United Kingdom; CHEST (Ms Patel), Glenview, IL; and Uniformed Services University of the Health Sciences, F. Edward Hebert School of Medicine (Dr Moores) Bethesda, MD. DISCLAIMER: CHEST Guidelines are intended for general information only, are not medical advice, and do not replace professional medical care and physician advice, which should always be sought for any medical condition. The complete disclaimer for this guideline can be accessed at: http://www.chestnet.org/Guidelines-and-Resources FUNDING/SUPPORT: This study was funded in total by internal funds from the American College of Chest Physicians. CORRESPONDENCE TO: Gregory Y.H. Lip, MD, Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart and Chest Hospital, Liverpool, United Kingdom; e-mail: gregory.lip@ liverpool.ac.uk Copyright 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. 1122 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] patients with one or more non-sex CHA2DS2-VASc stroke risk factors (score of 1 in a male or 2 in a female) (Strong recommendation, moderate quality evidence). Remark: Consideration of other less established clinical stroke risk factors, imaging (cardiac or cerebral), or biomarkers (urine, blood, or genetics) may re ne risk strati cation based on simple clinical factors. A complex risk schema using a variety of such data that could accurately place more patients in the low risk stratum not requiring anticoagulants than current simple clinically based scores (personalized medicine) should be the goal of future research, but it will be very dif cult to nd non- anticoagulated patient cohorts for prospective validation. 3. For patients with AF, we recommend bleeding risk assessment should be performed for all patients with AF at every patient contact and should initially focus on potentially modi able bleeding risk factors (Strong recommendation, low quality evidence). Remark: Modi able risk factors may include: Uncontrolled blood pressure; Labile INRs (in a patient taking VKA); Alcohol excess; Concomitant use of NSAIDs or aspirin in an anticoagulated patient; bleeding tendency or predisposition (eg, treat gastric ulcer, optimize renal or liver function, etc). 4. For patients with AF, we recommend use of the HAS-BLED score to address modi able bleeding risk factors in all AF patients. Those potentially at high risk (HAS-BLED score 3) warrant more frequent and regular reviews or follow-up (Strong recommendation, moderate quality evidence). Remark: Given that bleeding risk is highly dynamic, attention to modi able bleeding risk factors should be prioritized during every patient contact and review. 5. In VKA-treated patients, we suggest the use of the HAS-BLED score for bleeding risk assessment (Weak recommendation, low quality evidence). Remark: A high HAS-BLED score ($ 3) is rarely a reason to avoid anticoagulation. The individual modi able components of the score, when reviewed with the patient, can serve to ameliorate bleed risk. 6. For patients with AF, we recommend against antiplatelet therapy alone (monotherapy or aspirin in combination with clopidogrel) for stroke prevention alone, regardless of stroke risk (Strong recommendation, moderate quality evidence). Remark: Patients with AF might have other indications for antiplatelet drugs (eg, acute coronary syndrome, stents). 7. In patients with AF who are eligible for OAC, we recommend NOACs over VKA (Strong recommendation, moderate quality evidence). Remark: Patient and caregiver preferences, cost, formulary considerations, anticipated medication adherence or compliance with INR testing and dose adjustment should be incorporated into clinical decision-making. 8. In patients on VKAs with consistently low time in INR therapeutic range (eg, TTR < 65%), we recommend considering interventions to improve TTR or switching to NOACs (Strong recommendation, moderate quality evidence). Remark: Action required if TTR < 65% - implement additional measures (more regular INR tests; review medication adherence; address other factors known to in uence INR control; education/counselling) to improve INR control. 9. In patients with prior unprovoked bleeding, warfarin-associated bleeding, or at high risk of bleeding, we suggest using apixaban, edoxaban, or dabigatran 110 mg (where available) as all demonstrate signi cantly less major bleeding compared with warfarin (Weak recommendation, very low quality evidence). Remark: In patients with prior gastrointestinal bleeding apixaban or dabigatran 110 mg bid may be preferable as they are the only NOACs associated without an increased risk of gastrointestinal bleeding compared with warfarin. Remark: Dabigatran 150 mg twice daily recommended in patients at high risk of ischemic stroke as only agent/ dose with superior ef cacy compared with warfarin. However, bleeding risk would need to be assessed and patients monitored. 10. For patients with non-valvular AF, when VKAs are used, we suggest the target should be INR 2.0-3.0, with attention to individual TTR, ideally 70% (Ungraded consensus-based statement). Remark: Action required if TTR sub-optimal (ie, <65- 70%) - implement additional measures (more regular INR tests; review medication adherence; address other factors known to in uence INR control; education/counseling) to improve INR control or consider an NOAC. Remark: When possible, experienced specialized anticoagulation clinics should be utilized for VKA and INR management. 11. For patients with AF, we suggest the SAMe-TT2R2 score to aid decision-making to help identify patients likely to do well on VKA (Ungraded consensus-based statement). Remark: Those with score 0-2 are likely to achieve a good TTR. Those with score > 2 are less likely to achieve a good TTR and would require more regular INR checks, education/counseling and frequent follow- up, or alternatively, NOAC should be considered as a better management option if high medication adherence can be expected. 12. For patients with AF of greater than 48 h or unknown duration undergoing elective electrical or pharmacologic cardioversion, we recommend therapeutic anticoagulation with well-managed VKA (INR 2-3) or an NOAC using dabigatran, rivaroxaban, edoxaban, or apixaban for at least 3 weeks before cardioversion or a transesophageal echocardiography (TEE)-guided approach with abbreviated anticoagulation before cardioversion rather than no anticoagulation (Strong recommendation, moderate quality evidence). Remark: With NOACs adherence and persistence should be strongly emphasized. 13. For patients with AF of greater than 48 hours or unknown duration undergoing elective electrical or pharmacologic cardioversion, we recommend therapeutic anticoagulation (with VKA or NOAC) for at least 4 weeks after successful cardioversion to sinus rhythm rather than no anticoagulation, regardless of the baseline risk of stroke (Strong recommendation, moderate quality evidence). Remark: Decisions about anticoagulation beyond 4 weeks should be made in accordance with our risk- based recommendations for long-term antithrombotic therapy in recommendations 1 and 2, and not on the basis of successful cardioversion. 14. In patients in which LAA thrombus is detected on TEE, cardioversion postponed, and OAC continued for another 4-12 weeks, to allow thrombus resolution or endothelization, we suggest that a decision on whether a repeat TEE is performed should be individualized (Ungraded consensus-based statement). *15. For patients with AF of documented duration of 48 hours or less undergoing elective cardioversion (electrical or pharmacologic), we suggest starting anticoagulation at presentation (low-molecular-weight heparin or unfractionated heparin at full venous thromboembolism treatment doses) and proceeding to cardioversion rather than delaying cardioversion for 3 weeks of therapeutic anticoagulation or a TEE-guided approach (Weak recommendation, low quality evidence). *16. For patients with AF and hemodynamic instability undergoing urgent cardioversion (electrical or pharmacologic), after successful cardioversion to sinus rhythm, we suggest therapeutic anticoagulation (with VKA or full adherence to NOAC therapy) for at least 4 weeks rather than no anticoagulation, regardless of baseline stroke risk (Weak recommendation, low quality evidence). Remark: Decisions about long-term anticoagulation after cardioversion should be made in accordance with our risk-based recommendations for long-term antithrombotic therapy in recommendations 1 and 2. *17. For patients with AF and hemodynamic instability undergoing urgent cardioversion (electrical or pharmacologic), we suggest that therapeutic-dose parenteral anticoagulation be started before cardioversion, if possible, but that initiation of anticoagulation must not delay any emergency intervention (Weak recommendation, low quality evidence). *18. For patients with AF and hemodynamic instability undergoing urgent cardioversion (electrical or pharmacologic), after successful cardioversion to sinus rhythm, we suggest therapeutic anticoagulation for at least 4 weeks after successful cardioversion to sinus rhythm rather than no anticoagulation, regardless of baseline stroke risk (Weak recommendation, low quality evidence). Remark: Decisions about anticoagulation beyond 4 weeks should be made in accordance with our risk- based recommendations for long-term antithrombotic therapy in recommendations 1 and 2. 1124 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] *19. For patients with atrial utter undergoing elective or urgent pharmacologic or electrical cardioversion, we suggest that the same approach to thromboprophylaxis be used as for patients with atrial brillation undergoing cardioversion (Ungraded consensus-based statement). 20. In AF patients presenting with an ACS and/or undergoing PCI/stenting, we recommend assessment of stroke risk using the CHA2DS2-VASc score (Strong recommendation, moderate quality evidence). Remark: All such patients are not low risk and should be considered for concomitant OAC. 21. In AF patients presenting with an ACS and/or undergoing PCI/stenting, we suggest attention to modi able bleeding risk factors at every patient contact, and assessment of bleeding risk using the HAS-BLED score (Weak recommendation, low quality evidence). Remark: Where bleeding risk is high (HAS-BLED $ 3), there should be more regular review and follow-up. 22. In AF patients requiring OAC undergoing elective PCI/stenting, where bleeding risk is low (HAS-BLED 0-2) relative to risk for recurrent ACS and/or stent thrombosis, we suggest triple therapy for 1-3 months, followed by dual therapy with OAC plus single antiplatelet (preferably clopidogrel) until 12 months, following which OAC monotherapy can be used (Weak recommendation, low quality evidence). 23. In AF patients requiring OAC undergoing elective PCI/stenting, where bleeding risk is high (HAS- BLED 3), we suggest triple therapy for 1 month, followed by dual therapy with OAC plus single antiplatelet (preferably clopidogrel) for 6 months, following which OAC monotherapy can be used (Weak recommendation, low quality evidence). 24. In AF patients requiring OAC undergoing elective PCI/stenting, where bleeding risk is unusually high and thrombotic risk relatively low, we suggest use of OAC plus single antiplatelet (preferably clopidogrel) for 6 months, following which OAC monotherapy can be used (Weak recommendation, low quality evidence). Remark: Patients at unusually high bleeding risk may include patients with HAS-BLED $ 3 and recent acute bleeding event. High thrombotic risk may include those with left main stent, multivessel PCI/stenting, etc. 25. In AF patients requiring OAC presenting with an ACS, undergoing PCI/stenting, where bleeding risk is low (HAS-BLED 0-2) relative to risk for ACS or stent thrombosis, we suggest triple therapy for 6 months, followed by dual therapy with OAC plus single antiplatelet (preferably clopidogrel) until 12 months, following which OAC monotherapy can be used (Weak recommendation, low quality evidence). 26. In AF patients requiring OAC presenting with an ACS, undergoing PCI/stenting, where bleeding risk is high (HAS-BLED 3), we suggest triple therapy for 1- 3 months, followed by dual therapy with OAC plus single antiplatelet (preferably clopidogrel) up to 12 months, following which OAC monotherapy can be used (Weak recommendation, low quality evidence). 27. In AF patients requiring OAC presenting with an ACS, undergoing PCI/stenting where bleeding risk is unusually highandthromboticrisklow,wesuggestOAC plus single antiplatelet (preferably clopidogrel) for 6- 9 months, following which OAC monotherapy can be used (Weak recommendation, low quality evidence). Remark: Patients at unusually high bleeding risk may include patients with HAS-BLED $ 3 and recent acute bleeding event. High thrombotic risk may include those with left main stent, multivessel PCI/stenting, etc. 28. In AF patients with ACS or undergoing PCI in whom OAC is recommended, we suggest using VKA with TTR > 65-70% (INR range 2.0-3.0), or to use an NOAC at a dose licensed for stroke prevention in AF (Weak recommendation, low quality evidence). Remark: Only dabigatran 150 mg bid or (not licensed in USA) 110 mg bid or rivaroxaban 15 mg qd are currently supported by clinical trial evidence. An NOAC based strategy has lower bleeding risk compared to a VKA- based strategy. 29. In AF patients in which aspirin is concomitantly used with OAC, we suggest a dose of 75-100 mg qd with concomitant use of PPI to minimize gastrointestinal bleeding (Weak recommendation, low quality evidence). 30. In AF patients in which a P2Y12 inhibitor is concomitantly used with OAC, we suggest the use of clopidogrel (Weak recommendation, low quality evidence). Remark: Newer agents (eg, ticagrelor) can be considered where bleeding risk is low. Data on the combination of ticagrelor with either dabigatran 110 mg bid or 150 bid (without concomitant aspirin use) are available from the RE-DUAL PCI trial. *31. For patients with AF and stable coronary artery disease (eg, no acute coronary syndrome within the previous year) and who choose oral anticoagulation, we suggest OAC with either an NOAC or adjusted- dose VKA therapy alone (target international normalized ratio [INR] range, 2.0-3.0) rather than the combination of OAC and aspirin (Weak recommendation, low quality evidence). 32. In patients with AF in whom catheter ablation of AF or implantation of cardiac electronic implantable devices is planned, we suggest performing the procedure on uninterrupted VKA (within the INR therapeutic range), dabigatran or rivaroxaban (Weak recommendation, low quality evidence). 33. In patients in whom sinus rhythm has been restored, we suggest that long-term anticoagulation should be based on the patient s CHA2DS2-VASc thromboembolic risk pro le, regardless of whether sinus rhythm has been restored via ablation, cardioversion (even spontaneous), or other means (Weak recommendation, low quality evidence). 34. In AF patients with acute ischemic stroke, we suggest that very early anticoagulation (< 48 h) using heparinoids or VKA should not be used (Ungraded consensus-based statement). Remark: Heparinoids should not be used as bridging therapy in the acute phase of ischemic stroke because they appear to increase the risk of symptomatic intracranial hemorrhage without net bene t. The optimal timing of anticoagulation after acute ischemic stroke is unknown. 35. In AF patients with acute stroke without contraindications, we recommend that long-term oral anticoagulation is indicated as secondary prevention (Strong recommendation, high quality evidence). Remark: The optimal timing of anticoagulation early after acute ischemic stroke is unknown. Early use of NOACs shows promise but requires testing in randomized controlled trials. 36. In AF patients with acute ischemic stroke, we suggest that oral anticoagulation should usually be started within 2 weeks of acute ischemic stroke, but the optimal timing within this period is not known (Ungraded consensus-based statement). Remark: Although infarct size is clinically used to guide timing of anticoagulation, it is predictive of a higher risk of early recurrent ischemia, hemorrhagic transformation of the infarct, and poor outcome, so might not be helpful in determining the net bene t of early treatment. Remark: Anticoagulation with NOACs soon after stroke (earlier than 1 week) has not been tested in randomized trials, but shows promise in observational studies. 37. In patients with AF and high ischemic stroke risk, we suggest anticoagulation with an NOAC after acute spontaneous ICH (which includes subdural, subarachnoid, and intracerebral hemorrhages) after careful consideration of the risks and bene ts (Ungraded consensus-based statement). Remark: The balance of net bene t from long-term oral anticoagulation might be more favorable in those with deep ICH or without neuroimaging evidence of cerebral amyloid angiopathy. Remark: In ICH survivors with AF, clinicians should aim to estimate the risk of recurrent ICH (using ICH location and, where available, MRI biomarkers including cerebral microbleeds) and the risk of ischemic stroke. Remark: The optimal timing of anticoagulation after ICH is not known, but should be delayed beyond the acute phase (approximately 48 h) and probably for at least approximately 4 weeks. Randomized trials of NOACs and left atrial appendage occlusion are ongoing. 38. In ICH survivors at high risk of recurrent ICH (eg, those with probable cerebral amyloid angiopathy), we suggest left atrial appendage occlusion (Ungraded consensus-based statement). Remark: Cerebral amyloid angiopathy should be diagnosed using validated clinico-radiological criteria. 39. In patients with AF and symptomatic carotid stenosis (> 50%), we suggest carotid revascularization with endarterectomy or stenting in addition to OAC as indicated (Weak recommendation, moderate quality evidence). 40. In patients with AF and carotid stenosis treated with revascularization, we suggest OAC therapy, without long-term antiplatelet therapy (Ungraded consensus-based statement). Remark: There is limited evidence to guide the optimal treatment of patients with AF and carotid stenosis not requiring revascularization. Remark: Short-term concomitant antiplatelet therapy (dual or mono) is generally used in the immediate post- revascularization period (eg, 1-3 months). 1126 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] 41. For patients who present with a clinically documented episode of AF (12-lead ECG or other means, eg, external devices with validated rhythm detection), we suggest that the presence or absence of symptoms must not in uence the process of decision- making with regard to the need for anticoagulation based on risk strati cation (Ungraded consensus-based statement). 42. In cases of AHRE (atrial high-rate episodes) detected by a CIED of at least 5 min duration, we suggest that direct analysis of electrograms corresponding to AHRE is clinically indicated to exclude artifacts or other causes of inappropriate detection of atrial tachyarrhythmias or AF (Ungraded consensus-based statement). Remark: In patients with CIED-detected AHRE, a complete cardiological evaluation is indicated, with 12- lead ECG, general assessment of clinical conditions and clinical risk strati cation for stroke using CHA2DS2- VASc score. Remark: There is no evidence in support or against prescription of oral anticoagulants in patients at risk of stroke (intermediate to high risk according to CHA2DS2-VASc) who present with AHREs, corresponding to atrial tachyarrhythmias/AF at electrograms assessment of less than 24 h duration. 43. In patients with AF, we suggest prescription of oral anticoagulants could be considered as a result of an individualized clinical assessment taking into account overall AHRE burden (in the range of hours rather than minutes) and speci cally, the presence of AHRE > 24 h, individual stroke risk (using CHA2DS2- VASc), predicted risk bene t of oral anticoagulation and informed patient preferences (Ungraded consensus-based statement). Remark: In patients with CIED-detected AHRE, continued patient follow-up is recommended, preferentially combining clinical follow-up with remote monitoring of the CIED or else more frequent device interrogation than standard for CIED follow-up, to detect the development of clinical AF (symptomatic or asymptomatic), to monitor the evolution of AHRE or AF burden and speci cally the transition to AHRE lasting more than 24 h, onset or worsening of heart failure, or any clinical change that might suggest a change in clinical pro le or clinical conditions. 44. For patients with atrial utter, we suggest that antithrombotic therapy decisions follow the same risk-based recommendations as for AF (Ungraded consensus-based statement). 45. For women receiving OAC for prevention of stroke/TE in AF who become pregnant, we suggest discontinuation of OAC with a VKA between weeks 6 and 12 and replacement by LMWH twice daily (with dose adjustment according to weight and target anti- Xa level 4-6 h post-dose 0.8-1.2 U/mL), especially in patients with a warfarin dose required of > 5 mg/day (or phenprocoumon > 3 mg/day or acenocoumarol > 2 mg/day). OAC should then be discontinued and replaced by adjusted-dose LMWH (target anti-Xa level 4-6 h post-dose 0.8-1.2 U/mL) in the 36th week of gestation (Ungraded consensus-based statement). 46. For women on treatment with long-term vitamin K antagonists who are attempting pregnancy and are candidates for LMWH substitution, we suggest performing frequent pregnancy tests and use LMWH instead of VKA when pregnancy is achieved rather than switching to LMWH while attempting pregnancy (Ungraded consensus-based statement). 47. For pregnant women, we suggest avoiding the use of NOACs (Ungraded consensus-based statement). Remark: For women on treatment with an NOAC we suggest switching to vitamin K antagonists, rather than switching to LMWH while attempting pregnancy. 48. For lactating women using warfarin, acenocoumarol, or UFH who wish to breast-feed, we suggest continuing the use of warfarin, acenocoumarol, LMWH, or UFH (Ungraded consensus-based statement) 49. For breast-feeding women, we suggest alternative anticoagulants rather than NOACs (Ungraded consensus-based statement). 50. For mild CKD (Stage II, CrCl 60-89 mL/min), we suggest that oral anticoagulation clinical decision- making and treatment recommendations match that of patients without CKD (Weak recommendation, very low quality evidence). 51. For moderate CKD (Stage III, CrCl 30-59 mL/ min), we suggest oral anticoagulation in patients with a CHA2DS2-VASc 2 with label-adjusted NOACs or dose-adjusted vitamin K antagonists (Weak recommendation, very low quality evidence). Remark: With VKA, good quality anticoagulation control (TTR > 65-70%) is recommended. 52. In severe non-dialysis CKD (Stage IV CrCl 15-30 mL/min), we suggest using VKAs and selected NOACs (rivaroxaban 15 mg QD, apixaban 2.5 mg bid, edoxaban 30 mg QD and [in USA only] dabigatran 75 mg bid) with caution, based on pharmacokinetic data (Ungraded consensus-based statement). 53. In end-stage renal disease (CrCl < 15 mL/min or dialysis-dependent), we suggest that individualized decision-making is appropriate (Ungraded consensus- based statement). 54. In end-stage renal disease (CrCl < 15 mL/min or dialysis-dependent, we suggest using well-managed VKA with TTR > 65-70% (Ungraded consensus-based statement). Remark: NOACs should generally not be used, although in USA, apixaban 5 mg bid is approved for use in AF patients receiving hemodialysis. Remark: In patients with CKD who initiate OAC, concomitant antiplatelet therapy including low-dose aspirin is likely to substantially elevate bleeding risk and should be used very judiciously. 55. In patients with AF at high risk of ischemic stroke who have absolute contraindications for OAC, we suggest using LAA occlusion (Weak recommendation, low quality evidence). Remark: When taking into account LAAO as a potential option, the risk of bleeding related to antiplatelet agents that need to be prescribed in the rst months has to be considered and the possibility to use NOACs. 56. In AF patients at risk of ischemic stroke undergoing cardiac surgery, we suggest surgical exclusion of the LAA for stroke prevention, but the need for long-term OAC is unchanged (Weak recommendation, low quality evidence). 57. In AF patients taking warfarin without high risk of thromboembolism or who do not have a mechanical valve, we suggest preoperative management without bridging (Weak recommendation, low quality evidence). 58. In AF patients on antithrombotic prophylaxis with warfarin with a high risk of thromboembolism or with a mechanical valve, we suggest preoperative management with bridging (Weak recommendation, low quality evidence). 59. In AF patients on antithrombotic prophylaxis with an NOAC, we suggest preoperative management without bridging (Weak recommendation, low quality evidence). 60. In AF patients who have previously refused OAC, we suggest reinforcing educational messages at each contact with the patient and revisit OAC treatment decisions (Ungraded consensus-based statement). Remark: Patient and physician treatment objectives often differ signi cantly and it is important to elicit from the patient what outcomes of OAC treatment are important to them. Remark: Explain the risk of stroke and bene t/risks of treatment in terms the patient can understand and signpost the patient to appropriate educational resources. Introduction Atrial brillation (AF) is the most common sustained cardiac arrhythmia, with an increasing prevalence and incidence with age. In adults aged > 40 years, there is a 1 in 4 lifetime risk of developing AF, with incident AF commonly related to various associated cardiovascular and noncardiovascular risk factors. AF without associated valvular heart disease (so-called nonvalvular AF ) is associated with a vefold increase in stroke risk (approximately 5% per year), but this risk is dependent on the presence of various stroke risk factors.1 Many of the risk factors leading to incident AF are also risk factors for ischemic stroke, and the promotion of an integrated or holistic approach to AF management is needed, incorporating stroke prevention, addressing symptoms and risk factor management.2 Stroke prevention is the principal priority in the holistic approach to AF management.1 Even since the last edition of the CHEST guidelines published in 2012,3 there have been substantial developments in AF thromboproprophylaxis, whether with regard to risk assessment, antithrombotic drugs, or nondrug approaches. It is clear that AF should not be considered in isolation, at the stage of detection, prevention, or treatment. For example, the majority of deaths in individuals with AF are from cardiac causes, including heart failure (HF), whereas stroke and bleeding represent a small subset of deaths, yet most interventions focus on stroke prevention.4 Thus, a more holistic approach is needed to take comorbidities and cross-disease sequelae of AF, bridging primary and secondary care.2 1128 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] Apart from stroke prevention ( A Avoid Stroke, use Anticoagulants), AF management requires patient-centered and symptom-directed decisions on rate or rhythm control ( B Better symptom management) as well as C Cardiovascular and other risk factor, and lifestyle The latter includes addressing risk factors (eg, cardiac ischemia, HF, hypertension, sleep apnea, diabetes) and lifestyle (eg, obesity, alcohol excess, stimulants). This simple ABC (Atrial brillation Better Care) approach would simplify an integrated approach to AF management in a holistic manner (Fig 1).2 This guideline focuses on stroke prevention and begins with a brief discussion of the methods used to develop these guidelines and the recommendations for antithrombotic therapy in patients with AF. Next, we provide our treatment recommendations, divided into the following sections:  Stroke and bleeding risk assessment  Antithrombotic therapy in patients with AF in general (includes patients with permanent, persistent, or paroxysmal AF)  Antithrombotic therapy in patients with AF in special situations: B Managing bleeding B Antithrombotic therapy for patients with AF undergoing cardioversion B Acute coronary syndrome (ACS) and stenting B Stable coronary artery disease B Rhythm control and electrophysiological procedures B Acute ischemic stroke, intracranial hemorrhage (ICH), embolic stroke of undetermined source (ESUS), carotid disease B Atrial high-rate episodes (AHREs) on devices B Chronic atrial utter B Pregnancy B Chronic kidney disease (CKD) B Valvular heart disease The article ends with a discussion of practical and patient-centered issues as well as suggestions for future research. Methods Expert Panel Composition The chair of the panel (G.Y.H.L.) was appointed and subsequently reviewed and approved by CHEST s Professional Standards Committee. Panelists were nominated by the chair based on their expertise relative to potential guideline questions. Con icts of Interest All panel nominees were reviewed for their potential con icts of interest (COIs) by CHEST s Professional Standards Committee. After review, nominees who were found to have no substantial COIs were approved, whereas nominees with potential intellectual and nancial COIs that were manageable were approved with management. Panelists approved with management were prohibited from participating in discussions or voting on recommendations in which they had substantial COIs. A grid was created listing panelists COIs for each recommendation for use during voting. Of note, the chair (G.Y.H.L.) recused himself from any voting on recommendations. The COI grid can be found in e-Table 1. Formulation of Key Questions Table 1 speci es the clinical questions being addressed in this article (in PICO [population, intervention, comparator, outcomes] format) and the types of studies included. Offer stroke prevention to patients with one or more risk factors for stroke Assess bleeding risk Decide on OAC (either a VKA with well-managed TTR or a NOAC Identify low risk patients Manage hypertension, heart failure, diabetes mellitus, cardiac ischemia, and sleep apnea Lifestyle changes: obesity reduction, regular exercise, and reduction of alcohol and stimulant use Patient psychological morbidity Consider patient values and preferences Patient-centered and symptom-directed decisions on rate vs rhythm control The ABC pathway for integrated care management A Avoid stroke Optimize stroke prevention B Better symptom management Treat symptoms C Cardiovascular and other comorbidities Manage risk factors Figure 1 The ABC pathway of integrated care management. ABC Atrial brillation Better Care; NOAC non-vitamin K antagonist oral anticoagulant drug; OAC oral anticoagulant; VKA vitamin K antagonist; TTR time in therapeutic range. (Adapted from Lip.2 ) TABLE 1 ] PICO Questions Section Question Patients Intervention Control Outcomes Methodology Burden of stroke in AF 1.2  Established clinical risk factors for ischemic stroke in AF (including AF burden)  Echocardiographic risk factors for ischemic stroke in AF  Potential novel risk factors for ischemic stroke in AF What are the risk factors for ischemic stroke and TE? Patients with AF - Established clinical risk factors - Risk factors on echocardiography - Novel risk factors Patients with chronic atrial utter NA NA Ischemic stroke Systemic TE Mortality Cohort studies Non-warfarin arms of RCTs 1.3 Risk strati cation for ischemic stroke and TE What risk strati cation schemes most accurately predict ischemic stroke and TE, and mortality? Patients with AF NA NA C-statistic NRI, IDI, DCA Absolute rates of ischemic stroke and TE Cohort studies Clinical prediction rules Antithrombotic Therapy 2.1 Patients with nonvalvular AF What are the bene ts and risks of different stroke prevention strategies? Patients with nonrheumatic AF - Low risk - Intermediate risk - High risk (including prior stroke) VKA No VKA - Death - All stroke - Ischemic stroke - Systemic embolism - Intracranial hem- orrhage (subdural, subarachnoid, and intracerebral) - Major extracranial hemorrhage - MI - Vascular death SR RCTs (Continued) Evidence-Based Medicine [ # C H E S T N O V E M B E R ] TABLE 1 ] (Continued) Section Question Patients Intervention Control Outcomes Methodology 2.1 Patients with nonrheumatic AF As above Antiplatelet drug (aspirin or other) No antiplatelet drug - Death - All stroke - Ischemic stroke - Systemic embolism - Intracranial hemorrhage (subdural, sub- arachnoid, and intracerebral) - Major extracranial hemorrhage - MI - Vascular death SR RCTs As above VKA Antiplatelet drug (aspirin or other) - Death - All stroke - Ischemic stroke - Systemic embolism - Intracranial hem- orrhage (subdural, subarachnoid, and intracerebral) - Major extracranial hemorrhage - MI - Vascular death SR RCTs As above Adjusted dose VKA Fixed minidose or low-intensity VKA  aspirin - Death - All stroke - Ischemic stroke - Systemic embolism - Intracranial hemorrhage (sub- dural, subarach- noid, and intracerebral) - Major extracranial hemorrhage - MI - Vascular death (Continued) chestjournal.org TABLE 1 ] (Continued) Section Question Patients Intervention Control Outcomes Methodology As above Clopidogrel aspirin Aspirin - Death - All stroke - Ischemic stroke - Systemic embolism - Intracranial hem- orrhage (subdural, subarachnoid, and intracerebral) - Major extracranial hemorrhage - MI - Vascular death SR RCTs As above NOACs VKA - Death - All stroke - Ischemic stroke - Systemic embolism - Intracranial hem- orrhage (subdural, subarachnoid, and intracerebral) - Major extracranial hemorrhage - MI - Vascular death SR RCTs Cohort studies As above NOAC Aspirin - Death - All stroke - Ischemic stroke - Systemic embolism - Intracranial hem- orrhage (subdural, subarachnoid, and intracerebral) - Major extracranial hemorrhage - MI - Vascular death SR RCTs Cohort studies (Continued) Evidence-Based Medicine [ # C H E S T N O V E M B E R ] TABLE 1 ] (Continued) Section Question Patients Intervention Control Outcomes Methodology As above Device therapy (WATCHMAN, PLAATO) VKA - Death - All stroke - Ischemic stroke - Systemic embolism - Intracranial hem- orrhage (subdural, subarachnoid, and intracerebral) - Major extracranial hemorrhage - MI - Vascular death - cardiac tamponade SR RCTs Cohort studies As above Nonpharmacologic therapies - Removal or liga- tion of left atrial appendage - Surgical or cath- eter ablation - Maze procedure VKA - Death - All stroke - Ischemic stroke - Systemic embolism - Intracranial hem- orrhage (subdural, subarachnoid, and intracerebral) - Major extracranial hemorrhage - MI - Vascular death - procedural / surgi- cal complications SR RCTs Cohort studies 2.2 Patients with valvular AF What are the bene ts and risks of different stroke prevention strategies? Patients with AF and rheumatic heart disease (ie, mitral stenosis) VKA No VKA - Death - All stroke - Ischemic stroke - Systemic embolism - Intracranial hem- orrhage (subdural, subarachnoid, and intracerebral) - Major extracranial hemorrhage - MI - Vascular death SR RCTs Cohort studies (Continued) chestjournal.org TABLE 1 ] (Continued) Section Question Patients Intervention Control Outcomes Methodology 2.3 Patients with prosthetic valves What are the bene ts and risks of different stroke prevention strategies? Patients with AF and prosthetic valves VKA No VKA - Death - All stroke - Ischemic stroke - Systemic embolism - Intracranial hem- orrhage (subdural, subarachnoid, and intracerebral) - Major extracranial hemorrhage - MI - Vascular death SR RCTs Cohort studies therapy for AF (or atrial utter) patients undergoing cardioversion 3.1 Urgent cardioversion What are the bene ts and risks of antithrombotic therapy for AF patients undergoing urgent cardioversion? Patients with AF undergoing urgent cardioversion Anticoagulation No anticoagulation - Death - All stroke - Ischemic stroke - Systemic embolism - Intracranial hem- orrhage (subdural, subarachnoid, and intracerebral) - Major extracranial hemorrhage - MI - Vascular death SR RCTs Cohort studies cardioversion What are the bene ts and risks of antithrombotic therapy for AF patients undergoing elective cardioversion? Patients with AF undergoing elective cardioversion Anticoagulation No anticoagulation - Death - All stroke - Ischemic stroke - Systemic embolism - Intracranial hem- orrhage (subdural, subarachnoid, and intracerebral) - Major extracranial hemorrhage SR RCTs Cohort studies (Continued) Evidence-Based Medicine [ # C H E S T N O V E M B E R ] TABLE 1 ] (Continued) Section Question Patients Intervention Control Outcomes Methodology - MI - Vascular death cardioversion What are the bene ts and risks of antithrombotic therapy when using TEE-guided cardioversion? Patients with AF undergoing TEE-guided cardioversion TEE-guided cardioversion Conventional anticoagulation - Death - All stroke - Ischemic stroke - Systemic embolism - Intracranial hem- orrhage (subdural, subarachnoid, and intracerebral) - Major extracranial hemorrhage - MI - Vascular death SR RCTs Cohort studies 5 Practical issues in the use of adjusted- dose VKA therapy 5.1 Optimal target INR What target INR provides the optimal balance between stroke prevention and bleeding in AF? Patients with AF INR, 2-3 Other - Death - All stroke - Ischemic stroke - Systemic embolism - Intracranial hem- orrhage (subdural, subarachnoid, and intracerebral) - Major extracranial hemorrhage - MI - Vascular death SR RCTs Cohort studies Patients with AF and valvular heart disease/ prosthetic valves INR, 2-3 Other - Death - All stroke - Ischemic stroke - Systemic embolism - Intracranial hem- orrhage (subdural, subarachnoid, and intracerebral) - Major extracranial hemorrhage - MI - Vascular death SR RCTs Cohort studies (Continued) chestjournal.org TABLE 1 ] (Continued) Section Question Patients Intervention Control Outcomes Methodology 5.1 TTR What is the association between TTR and outcomes in AF? Patients with AF Good TTR Poor TTR - Death - All stroke - Ischemic stroke - Systemic embolism - Intracranial hem- orrhage (subdural, subarachnoid, and intracerebral) - Major extracranial hemorrhage - MI - Vascular death SR RCTs Cohort studies 5.1 Monitoring of VKA therapy What is the most effective way to monitor VKA therapy? Patients with AF on VKA therapy Point-of-care testing, patient self-monitoring Usual care - Death - All stroke - Ischemic stroke - Systemic embolism - Intracranial hem- orrhage (subdural, subarachnoid, and intracerebral) - Major extracranial hemorrhage - MI - Vascular death SR RCTs Cohort studies Special situations 5.3a Patients with AF with stable coronary artery disease or peripheral arterial disease What are the bene ts and risks of adding aspirin therapy to VKA therapy? Patients with coronary artery disease or peripheral arterial disease OAC aspirin OAC - Death - All stroke - Ischemic stroke - Systemic embolism - Intracranial hem- orrhage (subdural, subarachnoid, and intracerebral) - Major extracranial hemorrhage - MI - Vascular death SR RCTs Cohort studies (Continued) Evidence-Based Medicine [ # C H E S T N O V E M B E R ] TABLE 1 ] (Continued) Section Question Patients Intervention Control Outcomes Methodology 5.3b Patients with AF presenting with ACS? As above Patients with ACS OAC aspirin clopidogrel Aspirin clopidogrel - Death - All stroke - Ischemic stroke - Systemic embolism - Intracranial hem- orrhage (subdural, subarachnoid, and intracerebral) - Major extracranial hemorrhage - MI - Vascular death SR RCTs Cohort studies 5.3c Patients with AF undergoing percutaneous coronary intervention with stenting As above Patients undergoing percutaneous coronary intervention stenting OAC aspirin clopidogrel Aspirin clopidogrel - Death - All stroke - Ischemic stroke - Systemic embolism - Intracranial hem- orrhage (subdural, subarachnoid, and intracerebral) - Major extracranial hemorrhage - MI - Vascular death SR RCTs Cohort studies 5.4 Patients with AF being treated in a rhythm control strategy What are the bene ts and risks of OAC therapy in patients treated with a rhythm control strategy? Patients being treated with a rhythm control strategy (eg, maze procedure, catheter ablation, electrophysiology procedure, pharmacologic) VKA, NOAC No OAC - Death - All stroke - Ischemic stroke - Systemic embolism - Intracranial hem- orrhage (subdural, subarachnoid, and intracerebral) - Major extracranial hemorrhage - MI - Vascular death SR RCTs Cohort studies (Continued) chestjournal.org TABLE 1 ] (Continued) Section Question Patients Intervention Control Outcomes Methodology management of OACs (including devices) Atrial high rate episodes on devices or monitors How should VKA therapy be managed for AF patients undergoing surgery/invasive procedure? Patients with AF on OAC therapy Bridging therapy with LMWH or IV heparin No bridging therapy - Death - All stroke - Ischemic stroke - Systemic embolism - Intracranial hem- orrhage (subdural, subarachnoid, and intracerebral) - Major extracranial hemorrhage - MI - Vascular death Cohort studies 5.6 Patients with AF presenting with an acute stroke AF patients with an ICH What is the optimal timing for initiation of anticoagulation? Patients with acute stroke Anticoagulation immediately Anticoagulation delayed - Death - All stroke - Ischemic stroke - Systemic embolism - Intracranial hem- orrhage (subdural, subarachnoid, and intracerebral) - Major extracranial hemorrhage - MI - Vascular death SR RCTs Cohort studies 5.7a Patients with AF who are pregnant What are the bene ts and risks of VKA therapy in pregnancy? Patients with AF who are pregnant VKA No VKA - Death - All stroke - Ischemic stroke - Systemic embolism - Intracranial hem- orrhage (subdural, subarachnoid, and intracerebral) - Major extracranial hemorrhage - MI - Vascular death SR RCTs Cohort studies (Continued) Evidence-Based Medicine [ # C H E S T N O V E M B E R ] TABLE 1 ] (Continued) Section Question Patients Intervention Control Outcomes Methodology 5.7b Patients with chronic atrial utter What are the bene ts and risks of different stroke prevention strategies? Patients with atrial utter As in 2.1 As in 2.1 - Death - All stroke - Ischemic stroke - Systemic embolism - Intracranial hem- orrhage (subdural, subarachnoid, and intracerebral) - Major extracranial hemorrhage - MI - Vascular death SR RCTs Cohort studies 6.1 Risk factors for bleeding on OAC therapy What are the risk factors for bleeding while on VKA therapy? Patients with AF on VKA therapy NA NA - Fatal hemorrhage - Intracranial hem- orrhage (subdural, subarachnoid, intracerebral) - Major extracranial hemorrhage - Minor bleeding Epidemiologic studies Cohort studies RCTs 6.2 Bleeding risk assessment What risk strati cation schemes most accurately predict the risk of bleeding? Patients with AF on OAC therapy NA NA C-statistic NRI, IDI, DCA Absolute rates of bleeding outcomes (as listed above) Clinical prediction rules 7 The patient What are the values and preferences of patients with AF regarding VKA therapy, risk of stroke, and risk of bleeding? Patients with AF NA NA Patient preferences Factors which affect patient preferences Quality of life RCTs Observational studies ACS acute coronary syndrome; AF atrial brillation; DCA decision curve analysis; ICH intracranial hemorrhage; IDI integrated discrimination index; INR international normalized ratio; LMWH low- molecular-weight heparin; MI myocardial infarction; NA not available; NOAC non-vitamin K antagonist oral anticoagulant drug; NRI net reclassi cation index; OAC oral anticoagulant; RCT randomized controlled trial; SR systematic reviews; TE thromboembolism; TEE transesophageal echocardiography; TTR time within therapeutic range; VKA vitamine K antagonist. chestjournal.org TABLE 2 ] CHEST Grading System Grade of Recommendation Bene t vs Risk and Burdens Methodologic Strength of Supporting Evidence Implications Strong recommendation, High quality evidence Bene ts clearly outweigh risk and burdens, or vice versa We are very con dent that the true effect lies close to that of the estimate of the effect Recommendation can apply to most patients in most circumstances. Further research is very unlikely to change our con dence in the estimate of effect Strong recommendation, Moderate-quality evidence Bene ts clearly outweigh risk and burdens, or vice versa We are moderately con dent in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Recommendation can apply to most patients in most circumstances. Higher quality research may well have an important impact on our con dence in the estimate of effect and may change the estimate Strong recommendation, Low quality evidence Bene ts clearly outweigh risk and burdens, or vice versa Our con dence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. Recommendation can apply to most patients in many circumstances. Higher quality research is likely to have an important impact on our con dence in the estimate of effect and may well change the estimate Strong recommendation, very low quality evidence Bene ts clearly outweigh risk and burdens, or vice versa We have very little con dence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect Recommendation can apply to most patients in many circumstances. Higher quality research is likely to have an important impact on our con dence in the estimate of effect and may well change the estimate Weak (conditional) recommendation, High quality evidence Bene ts closely balanced with risks and burden We are very con dent that the true effect lies close to that of the estimate of the effect The best action may differ depending on circumstances or patients or societal values. Further research is very unlikely to change our con dence in the estimate of effect Weak (conditional) recommendation, Moderate-quality evidence Bene ts closely balanced with risks and burden We are moderately con dent in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Best action may differ depending on circumstances or patients or societal values. Higher quality research may well have an important impact on our con dence in the estimate of effect and may change the estimate Weak (conditional) recommendation, Low quality evidence Uncertainty in the estimates of bene ts, risks, and burden; bene ts, risk and burden may be closely balanced Our con dence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Other alternatives may be equally reasonable. Higher quality research is likely to have an important impact on our con dence in the estimate of effect and may well change the estimate (Continued) Evidence-Based Medicine [ # C H E S T N O V E M B E R ] Consistent with the ninth edition of the guideline, the outcomes most relevant to patients with AF include death, nonfatal stroke, systemic embolism, nonfatal major extracranial bleeding, and the burden and lifestyle limitations associated with outpatient antithrombotic To facilitate decision-making, the term stroke in this guideline includes both ischemic stroke and hemorrhagic stroke, which together with systemic embolism was the principal outcome in most stroke prevention trials. Additional considerations were all- cause and cardiovascular mortality. For bleeding outcomes, we focused on major bleeding, which was the principal safety outcome in most stroke prevention trials. Major bleeding included intracranial bleeding, the most severe and disabling form of anticoagulant-related bleeding. Literature Searches and Study Selection To inform our guideline development, we searched for relevant articles published since the last formal literature search performed for the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th Edition), which were published in 2012.3 Searches were also conducted speci cally for existing guidelines and systematic reviews. In cases in which existing, good quality systematic review(s) were retrieved, the results of the review informed our recommendations. Speci cally, for literature regarding the assessment of stroke risk in patients with AF, we searched MEDLINE via PubMed and the Cochrane Library for articles published from October 2009 to October 2017 using the search terms atrial brillation, atrial utter, risk assessment, risk factors, risk strati cation, stroke, and thromboembolism. For literature regarding prevention of stroke and thromboembolism in patients with AF, we searched MEDLINE via PubMed and the Cochrane Library for articles published from January 1, 2007, to October 2017 using the search terms coumarins, warfarin, dicumarol, phenprocoumon, acenocoumarol, fondaparinux, idraparinux, aspirin, tri usal, indobufen, dabigatran, ximelagatran, rivaroxaban, apixaban, ticlopidine, clopidogrel, catheter ablation, watchman, PLAATO, cardioversion, atrial brillation, and atrial utter. Titles and abstracts of the search results were reviewed independently and in parallel to identify potentially relevant articles based on the inclusion and exclusion criteria from the PICO elements. Discrepancies were resolved by discussion. Studies deemed eligible then underwent a second round of full-text screening following the same methodology used during title/abstract review. Important data from each included study were then extracted into structured evidence tables. Risk of Bias Assessment The methodologist assessed the risk of bias in all included studies. The Cochrane Risk of Bias tool was used to assess the risk of bias for randomized controlled trials (RCTs)5 and the Risk of Bias in Non- randomized Studies of Interventions (ROBINS-I) tool to evaluate risk of bias for observational studies.6 In cases in which existing systematic reviews were available, we used the Documentation and Appraisal Review Tool to assess methodological quality.7 Meta-analysis When individual studies were available or an existing meta-analysis needed to be updated, we used the Cochrane Collaboration Review Manager, version 5.2,8 to pool the results across individual studies. We used a random-effects model and the method of DerSimonian and Laird to pool the individual estimates.9 Risk ratio (RR) was used to report the results for dichotomous outcomes and mean difference for continuous outcomes with accompanying 95% CIs. Statistical TABLE ] (Continued) Grade of Recommendation Bene t vs Risk and Burdens Methodologic Strength of Supporting Evidence Implications Weak (conditional) recommendation, very- low quality evidence Uncertainty in the estimates of bene ts, risks, and burden; bene ts, risk and burden may be closely balanced We have very little con dence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect Other alternatives may be equally reasonable. Higher quality research is likely to have an important impact on our con dence in the estimate of effect and may well change the estimate Ungraded consensus-based suggestions Ungraded Consensus- Based Statement Uncertainty due to lack of evidence but expert opinion that bene ts outweigh risk and burdens or vice versa Insuf cient evidence for a graded recommendation Future research may well have an important impact on our con dence in the estimate of effect and may change the estimate heterogeneity of the pooled results was assessed using the Higgins I2 and the c2 tests. A Higgins I2 value of $ 50% or c2 P < .05 was considered to represent signi cant heterogeneity. Assessing the Overall Quality of the Evidence The overall certainty (quality) of the evidence was assessed for each critical or important outcome of interest using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) Evidence pro les were created using the Guideline Development Tool, which categorized the overall quality of the body of evidence into 1 of 4 levels: high, moderate, low, or very low. Drafting Recommendations The panel drafted and graded recommendations based on the results of the meta-analyses and evidence pro les. Recommendations were graded according to CHEST s grading system, which uses the GRADE approach (Table 2).11,12 The recommendations were either strong or weak according to this approach. Strong recommendations use the wording we recommend and weak recommendations use the wording we suggest. The implications of the strength of recommendation are summarized in e-Table 2. In instances in which there was insuf cient evidence, but a clinically relevant area was felt to require a guiding comment, a weak suggestion was developed and Ungraded Consensus-Based Statement replaced the grade.13 In developing our treatment recommendations, we attempted to account for patient values and preferences regarding these outcomes, and had 2 patient advocates (Mellanie True Hills and D. A. L.) who participated in the panel discussion, and speci cally addressed patient-centered issues. Consensus Development All drafted recommendations and suggestions were presented to the panel in an anonymous online voting survey to reach consensus and gather feedback. Panelists were requested to indicate their level of agreement on each statement based on a 5-point Likert scale derived from the GRADE grid.14 Panelists with COIs related to the individual recommendations recused themselves from voting on those statements. Of note, the chair (G. Y. H. L.) recused himself from any voting on recommendations. According to CHEST policy, each recommendation and statement required a 75% voting participation rate and at least 80% consensus to pass. Any recommendation or suggestion that did not meet these criteria was revised by the panel based on the feedback, and a new survey that incorporated those revisions was completed. Peer Review Process Reviewers from the Guideline Oversight Committee, the CHEST Board of Regents, and the CHEST journal reviewed the methods used and the content of the manuscript for consistency, accuracy, and completeness. The manuscript was revised according to feedback from the reviewers. Stroke Risk in AF The extensive data on epidemiologic burden of stroke associated with AF and well as the pathophysiology is detailed in e-Appendix 1. It is beyond the scope of this document to consider the epidemiology of all comorbidities in AF. In summary, health-care systems face increasing prevalence, incidence, and lifetime risk of AF, which is as high as 1 in 4 in contemporary studies in high-income Epidemiologic studies largely represent Western countries and white populations.16 However, reported prevalence varies substantially by world region (e-Fig 1) and with more rigorous screening methods to detect AF. Individuals with AF have increased risk of stroke (fourfold to vefold increase), HF (twofold to threefold fold increase), and mortality (twofold increase) (see e-Appendix 1). Patients with AF also experience higher rates of morbidity and hospital admissions, as well as early dementia. The high AF-attributable risk of stroke, especially in the elderly, is evident since at least 1 in 3 to 4 individuals with an ischemic stroke, and > 80% of those with ischemic stroke of cardioembolic subtype, also have Overall, non-white ethnicity shows evidence of association with lower risk of incident AF. Several of the risk factors for incident AF are also risk factors for stroke in AF.18 Primary prevention strategies for AF have not been conclusively proven in randomized trials, and opportunistic screening is the recommended strategy to detect AF at the population-level.19 A systematic review of the associations of 23 cardiovascular risk factors and incident AF including 20,420,175 participants and 576,602 AF events, respectively, found hypertension, obesity, taller height, and coronary heart disease showed consistent, direct associations with incident AF.18 Ethnic differences in comorbidities in AF patients have been reported Hypertension is the leading comorbid risk factor and is equally distributed in different races. Coronary heart disease seems more common in whites and the Middle East, than in Asians. The annual risk of AF-associated stroke in Asians is higher than that in and the risk of stroke may start to increase at a younger age in Asians.37 Classi cation of AF AF is classi ed as paroxysmal (self-terminating within 7 days), persistent (continuous for > 7 days), long- standing persistent (continuous for > 1 year), or permanent (chronic). AF becomes increasingly persistent and resistant to therapy over time, perhaps due to the development of atrial brosis, as well as other pathophysiological processes (e-Fig 2). 