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), 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.


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 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.


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).


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: 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.


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).


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.


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 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 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.


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.


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.


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?


(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 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 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 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 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?


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 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 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.


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 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.


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.


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.


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.


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.


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.


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.


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).


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). AF and atrial utter frequently co-exist, and share similar risk factors for arrhythmia development and stroke risk.39 Lone AF 1142 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] is a low risk patient group that is a diagnosis of exclusion, after ensuring no comorbidity risk factors are Lone atrial utter (without any recognizable underlying disease), like lone AF, is also rare: only 2% of atrial utter patients.41 The role of anticoagulation in atrial utter has not been assessed in clinical trials, but since individuals with atrial utter often have concomitant AF or are at increased risk of developing AF, the risk of stroke and thromboembolism is assumed to be the same, and the same risk strati cation approaches are recommended. Risk Factors for Ischemic Stroke: Clinical Risk Factors for Ischemic Stroke in AF: Although AF is an independent risk factor for stroke, not all patients with AF have equal stroke risk. To correctly assess the risk of stroke in order to inform anticoagulation, risk prediction or strati cation tools have been developed, based on the risk factors most strongly and consistently associated with stroke. A systematic review of stroke risk factors found that prior stroke or transient ischemic attack (TIA) (15 of 16 studies positive; RR, 2.86), hypertension (11 of 20 studies positive; RR, 2.27), aging (9 of 13 studies positive; RR, 1.46 per decade increase), structural heart disease (9 of 13 studies positive; RR, 2.0), and diabetes (9 of 14 studies positive; RR, 1.62) were independent predictors of stroke.


A systematic review of stroke risk factors found that prior stroke or transient ischemic attack (TIA) (15 of 16 studies positive; RR, 2.86), hypertension (11 of 20 studies positive; RR, 2.27), aging (9 of 13 studies positive; RR, 1.46 per decade increase), structural heart disease (9 of 13 studies positive; RR, 2.0), and diabetes (9 of 14 studies positive; RR, 1.62) were independent predictors of stroke. Supportive evidence was found for sex (8 of 22 studies positive; RR, 1.67), vascular disease studies positive; RR, 1.85).42 Nonparoxysmal AF is associated with a highly signi cant increase in thromboembolism (multivariable adjusted hazard ratio In individuals with HF, AF is associated with worse prognosis than sinus rhythm.44,45 HF is an independent predictor of stroke/thromboembolism, mortality, and other clinical outcomes in individuals with AF, compared with no HF.46 Moreover, HF is a predictor of development of AF and has been incorporated in tools for risk prediction of incident AF.47 All-cause mortality is higher in AF patients with HF with reduced ejection fraction compared with HF with preserved ejection although stroke risk (RR, 0.85; 95% CI, 0.70-1.03; P .094) and HF hospitalization (RR, 1.21; 95% CI, 0.96-1.53; P .115) are not signi cantly different.48 CKD is an independent predictor of risk of stroke/ thromboembolism. AF patients with an estimated glomerular ltration rate < 60 mL/min compared with those with an estimated glomerular ltration rate $ 60 mL/min have increased risk of stroke/ P < .001), with a 0.41% (0.17%-0.65%) annual increase in rate for a 10 mL/min decrease in renal function.49 The risk is higher in individuals requiring renal replacement therapy (HR, 1.83; 95% CI, 1.57-2.14; P < .001).


AF patients with an estimated glomerular ltration rate < 60 mL/min compared with those with an estimated glomerular ltration rate $ 60 mL/min have increased risk of stroke/ P < .001), with a 0.41% (0.17%-0.65%) annual increase in rate for a 10 mL/min decrease in renal function.49 The risk is higher in individuals requiring renal replacement therapy (HR, 1.83; 95% CI, 1.57-2.14; P < .001). There is also an increased risk of bleeding in individuals with AF and CKD, compared with those without CKD.50 Conversely, AF is associated with an increased risk of The clinical relevance of renal function is not only for risk prediction but also for choice of anticoagulation and other (see AF and CKD section). Over the last decade, rigorous detection strategies have shown that the prevalence of AF in cryptogenic stroke is likely to be as high as 30%.55 A systematic review and meta-analysis after TIA has shown a pooled AF detection rate for all methods of 4% (95% CI, 2-7).56 Echocardiographic Risk Factors: The role of echocardiography in evaluation before cardioversion or ablation, and in predicting the presence of left atrial appendage (LAA) thrombus is dealt with in sections Cardioversion and Catheter or Surgical Ablation, Electrophysiological Procedures. There may also be a role in evaluating thromboembolic risk strati cation to select appropriate antithrombotic therapy. e-Table 4 summarizes major studies which have shown an association between transthoracic echocardiography (TTE) parameters and ischemic stroke. However, there are very limited data to suggest that there would be any incremental clinical bene t in risk prediction, and moreover there is no evidence that management (in terms of oral anticoagulant [OAC]) would be changed.57 Nevertheless, the most consistent independent predictor of ischemic stroke on TTE is the presence of moderate- severe left ventricular systolic dysfunction.


However, there are very limited data to suggest that there would be any incremental clinical bene t in risk prediction, and moreover there is no evidence that management (in terms of oral anticoagulant [OAC]) would be changed.57 Nevertheless, the most consistent independent predictor of ischemic stroke on TTE is the presence of moderate- severe left ventricular systolic dysfunction. In patients undergoing transesophageal echocardiography (TEE), and left atrial spontaneous echo are both associated with increased thromboembolism, as well as the presence of low LAA velocities and complex aortic plaque; however, the same limitations as for TTE parameters apply.57 Biomarkers: e-Table 5 summarizes important studies involving currently available biomarkers ( biological markers ) that have shown associations with stroke and thrombosis in AF, but both study design and scale of the studies limit possible conclusions. Caveats with the use of these biomarkers include the inter- and intra-patient and assay variability; some have a diurnal variation and can be highly in uenced by associated comorbidities and drug therapies. Many biomarkers are nonspeci c for a particular end point and can be equally predictive not only of stroke but bleeding, death, hospitalization, HF, etc, as well as noncardiac conditions (eg, glaucoma). The importance of biomarkers probably lies in the very low risk strata of clinical scores (eg, CHA2DS2-VASc 0-1 group) where they may in uence the decision to anticoagulate, yet there are limited data available in these patients. There are several other hurdles, including variations in availability in health-care systems, biomarker assays, access to laboratories, biomarkers diurnally, by comorbidities and by anticoagulation and other therapies. For these reasons, the clinical application of biomarkers in management of AF is unlikely to be signi cant.


For these reasons, the clinical application of biomarkers in management of AF is unlikely to be signi cant. Other Potential Novel Risk Factors for Ischemic Stroke in AF: As with established risk factors, novel risk factors may improve prediction of thromboembolic risk in AF patients, where current risk scores are These novel factors include clinical risk factors (eg, burden of AF), serum biomarkers (eg, N-terminal pro B-type natriuretic peptide), imaging (eg, left atrial brosis on cardiac MRI), and echocardiography (eg, left atrial volume index and longitudinal strain). However, these factors are currently neither proven to signi cantly add to risk prediction, nor likely to in uence the decision to anticoagulate. Risk Strati cation for Stroke and Thromboembolism in AF: A comparison of features included in various published stroke risk strati cation schemes in AF is shown in e-Table 6. A summary of studies comparing the various stroke risk strati cation schema is available in e-Table 7. The risk strati cation scheme commonly used in many guidelines is the CHA2DS2-VASc (congestive heart failure, hypertension, age $ 75 years [doubled], diabetes, stroke/TIA/thromboembolism [doubled], vascular disease [prior myocardial infarction (MI), peripheral arterial disease (PAD), or aortic plaque], age 65-74 years, sex category [female]) score.1 All risk schemes based on clinical risk factors have broadly similar predictive value for high risk patients who sustain stroke and thromboembolism events (all c-indexes approximately 0.60-0.65). Adding more and more clinical variables and complexity (ie, simple vs more complex clinical risk scores) would only modestly increase the c-index to approximately 0.65 to 0.70. Many score comparisons focus on identi cation of high risk and do not focus on low risk end of the spectrum and so are not helpful for decision-making on whether to anticoagulate.


Many score comparisons focus on identi cation of high risk and do not focus on low risk end of the spectrum and so are not helpful for decision-making on whether to anticoagulate. Event rates per score point varies according to study setting, ethnicity, cohort, and community vs hospitalized population, etc (as might be expected).61 Also, reported events depends on use of highly selected clinical trial cohort vs real-world unselected, and anticoagulated vs non-anticoagulated patients.62 Mortality rates from observational cohorts may also include fatal strokes as postmortems are not mandated, outcomes are nonadjudicated (as in clinical trials), and cerebral imaging is not performed. Analytical methodology matters and outcomes depend on thresholds for treatment, varying risk pro le during the study (which does not remain static), and statistical analysis Some analyses which exclude patients on anticoagulants are awed by conditioning on the future methodology, and follow-up can be dependent on continuation in a (US) health-care plan. Ethnic differences are also evident in stroke risk related to AF. In a Taiwanese cohort, the risk of stroke was 1.78% per year in patients aged 50 to 64 years and a The risk exceeds the threshold for OAC use for stroke prevention. A modi ed CHA2DS2- VASc score has been proposed, assigning one point for The modi ed CHA2DS2- VASc score performed better than the CHA2DS2-VASc score in predicting ischemic stroke assessed by c-indexes and net reclassi cation index. For patients having a modi ed CHA2DS2-VASc score of 1 (males) or 2 (females) because of the resetting of the age threshold, use of warfarin was associated with a 30% lower risk of ischemic stroke and a similar risk of ICH compared with no treatment. Net clinical bene t analyses also favored the use of warfarin in different weighted models.


Net clinical bene t analyses also favored the use of warfarin in different weighted models. These ndings suggest that the age-based treatment threshold for stroke prevention may need to be reset in East Adding biomarkers would (statistically) improve prediction, but c-indexes are still approximately 0.65 to 0.70. Recent studies in real-world cohorts do not support the clinical usefulness of biomarker-based scores over clinical risk scores such as the CHA2DS2-VASc score. The use of biomarkers has to balance the assay availability, laboratory variability, costs, and added complexity and lower practicality for everyday use. Also, many biomarker studies are based on anticoagulated 1144 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] highly selected clinical trial cohorts, with all included subjects already in the high risk group (CHA2DS2-VASc or CHADS2 [congestive heart failure, hypertension, age, diabetes, stroke (doubled)] score of 2 or greater). There are few/no studies on non-anticoagulated AF patients, to ascertain the true impact of biomarkers on (non- anticoagulation treated) stroke rates. Current studies do not inform whether the biomarkers will discriminate/ identify low risk in lower/intermediate risk patients who are not anticoagulated. Rather than focus on identifying high risk, the focus should be on initially identifying low risk patients.


Rather than focus on identifying high risk, the focus should be on initially identifying low risk patients. A low risk categorization by the CHA2DS2-VASc (0 in males and 1 in females) consistently identi es low risk patients, with event rates around 1% per year or under, notwithstanding the possible need to re-categorize the age 65 to 74 years criterion in Asians.65 The majority of published studies and systematic reviews suggest that the CHA2DS2-VASc score is generally better than CHADS2, Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA), and CHADS2 score plus age 65-74 years, used in Canadian guidelines (CHADS65) in identifying low risk patients, although the proportion of the population assigned as low risk is small. However, there are con icting data in different cohorts for performance of the ATRIA score (United Kingdom Clinical Practice Research Datalink [UK CPRD] and Swedish cohorts vs Danish and Taiwan cohorts). Differences between the ATRIA and CHA2DS2-VASc disappear when cut-points are optimized for stroke risk of the cohort. There are discrepancies between individual studies on the relative performance of ATRIA and CHA2DS2-VASc scores in identifying low risk patients, but the CHA2DS2-VASc score is easier to calculate. Rather than using risk scores in a categorical manner recognizing the various limitations of scores to predict high risk patients who sustain events and given that for each risk strata or given risk score point, we recognized there is wide variation in reported event rates based on reported study clinical setting, patient population, ethnicity, etc. Notwithstanding that the default should be stroke prevention for all AF patients unless deemed to be low risk, the focus should be to use scores to initially identify low risk patients who do not need antithrombotic therapy, rather than focus on identi cation of high risk patients.


Notwithstanding that the default should be stroke prevention for all AF patients unless deemed to be low risk, the focus should be to use scores to initially identify low risk patients who do not need antithrombotic therapy, rather than focus on identi cation of high risk patients. Prior guidelines have also opted for the CHA2DS2-VASc score to de ne a low risk group. The C in CHA2DS2-VASc refers to recent decompensated HF, irrespective of the ejection fraction (thus including HF with reduced ejection fraction or HF with preserved ejection fraction) or the presence of moderate-severe left ventricular systolic impairment on cardiac imaging, whether symptomatic or asymptomatic. The H refers to history of hypertension or uncontrolled BP, while S refers to stroke, systemic embolism, or a con rmed diagnosis of TIA. V refers to complicated vascular disease, including MI or PAD, or if performed, the presence of complex aortic plaque on TEE. Female sex (Sc criterion) is only relevant as a risk modi er if age > 65 or additional associated risk factors are present, given that females age < 65 with no other risk factors are not at excess stroke risk.66 Stroke risk is also dynamic, and risk should be re-assessed at every patient contact. This was seen in a study where the delta CHA2DS2VASc score, representing the change in stroke risk between between baseline and follow-up), was the best predictor for ischemic stroke.67 A stepwise approach to thromboprophylaxis would allow initial identi cation of low risk using CHA2DS2- VASc (Step 1), following which stroke prevention can be offered to all others (Step 2) irrespective of stroke point score or biomarkers used. This approach uses stroke risk scores in a reductionist manner to aid decision-making, and balances simplicity and practicality (and costs). Recommendations 1.


This approach uses stroke risk scores in a reductionist manner to aid decision-making, and balances simplicity and practicality (and costs). 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, stroke prevention should be offered to those AF 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.


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. Bleeding Risk in AF Observational Studies The rates of major bleeding on vitamin K antagonists (VKAs) among observational cohorts are shown in e-Table 8 and demonstrate highly variable rates, ranging Nevertheless, there is signi cant heterogeneity between the study population characteristics, the inclusion of inception vs experienced OAC cohorts, signi cant disparity in the exposure period (follow-up) and differences in the de nitions of major bleeding employed. In addition, information on the speci c risks of bleeding of the individual cohorts, using a validated bleeding risk score, are lacking, the de nitions of major bleeding were often not provided, and the quality of anticoagulation, such as time in therapeutic range (TTR), is generally lacking. Therefore, direct comparison of the rates of major bleeding on VKA between observational cohorts and with RCTs is problematic. Clinical Trials The de nitions of major bleeding are available in most clinical trials, especially in the non-vitamin K antagonist oral anticoagulant drug (NOAC) trials where International Society on Thrombosis and Haemostasis de nitions were used.71 Before the NOAC era, the rates of major bleeding due to VKA were generally in the range of 1% to 3% per year (e-Table 9). In the 5 NOAC the annual rates of major bleeding of warfarin were between 3% and 4% (Table 3). Data from NOACs trials are more reliable, because patients were randomized to treatment, the majority were double- blinded, and the quality of anticoagulation (such as TTR) was generally better than observational studies.


Data from NOACs trials are more reliable, because patients were randomized to treatment, the majority were double- blinded, and the quality of anticoagulation (such as TTR) was generally better than observational studies. The risk of major bleeding on NOACs, especially the low-dose regimen (dabigatran 110 mg and edoxaban 30 mg), was generally lower than that on warfarin, except 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) trial.73 Risk Factors for Bleeding With NOAC, VKA, and Antiplatelet Therapy: Numerous risk factors for bleeding among AF patients receiving antithrombotic therapy have been identi ed and incorporated into bleeding risk scores (see section on Use of Bleeding Risk Scores). Bleeding risk varies from person to person depending on their pre-existing comorbidities, current antithrombotic regimen and adherence, concomitant medication, and lifestyle choices. Many of these factors cannot be altered but some are modi able or potentially modi able (Fig 2). In order to reduce antithrombotic treatment-associated bleeding, it is important to recognize that bleeding risk is also dynamic and should be reassessed at every patient review. While modi able bleeding risk factors that can be changed or managed should clearly be addressed as part of a holistic approach to AF patient assessment and management, nonmodi able bleeding risks are important drivers of bleeding events when occurring synergistically with An approach to bleeding risk assessment soley based only on modi able bleeding risk factors is an inferior assessment strategy compared with use of a formal bleeding risk score.78-80 BP Control: Good control of BP is vital to reduce the risk of stroke and is essential to decrease the risk of bleeding on antithrombotic therapy; adherence to current guidelines on the management of hypertension should be followed.


While modi able bleeding risk factors that can be changed or managed should clearly be addressed as part of a holistic approach to AF patient assessment and management, nonmodi able bleeding risks are important drivers of bleeding events when occurring synergistically with An approach to bleeding risk assessment soley based only on modi able bleeding risk factors is an inferior assessment strategy compared with use of a formal bleeding risk score.78-80 BP Control: Good control of BP is vital to reduce the risk of stroke and is essential to decrease the risk of bleeding on antithrombotic therapy; adherence to current guidelines on the management of hypertension should be followed. Anticoagulation Control: Among patients receiving VKA, maintenance of an international normalized ratio (INR) in the therapeutic range (2.0-3.0) is essential. The proportion of time spent in this range (TTR) should be at least 65% but the ultimate aim/target should be 100% (see Optimal INR Target Range section). The risk of bleeding increases when the INR exceeds 3.0, particularly for ICH risk when INR > 3.5.81-86 INR control can potentially be improved by more frequent monitoring and review of factors in uencing INR control (diet-, alcohol-, and drug-interactions). There is evidence that improving patient education about INR control,87 INR management by dedicated anticoagulation clinics with experienced personnel,88-90 and self-monitoring/self-management in selected can increase TTR. Increasing patient s awareness of the importance of OAC medication adherence and the potential bleeding risks associated with overdose are also essential to minimize bleeding complications.


Increasing patient s awareness of the importance of OAC medication adherence and the potential bleeding risks associated with overdose are also essential to minimize bleeding complications. 1146 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] TABLE 3 ] Risk Factors, Risk Categories and Bleeding Events in the Validation Cohorts Risk Score Risk Factors (Score for Each Factor) Risk Categories Bleeding Events in Validation Cohort (per 100 patient-years) Low Intermediate High Low Intermediate High Agea ; biomarkersa (GDF-15 or cystatin C/CKD-EPI, cTnT-hs, and Hb); previous bleeda history (2); Y renal function (1); APT (1) Anemia (3); severe renal disease (3); age $ 75 [SBP (1); severe renal/hepatic disease (1 each); stroke (1); bleeding (1); labile INR (1); age > Hepatic/renal disease (1); ethanol abuse (1); malignancy; age > 75 y (1); YPlt (1); re-bleeding risk (2); [BP (1); anemia (1); genetic factors Shireman et al102 Age $ 70 y (0.49); female (0.31); previous bleed (0.58); recent bleed (0.62); alcohol/drug abuse Y reduced/decreased; [ elevated/increased; ABC Atrial brillation Better Care; APT antiplatelet therapy; ATRIA Anticoagulation and Risk Factors in Atrial Fibrillation; CKD-EPI Chronic Kidney Disease Epidemiology Collaboration; cTnT-hs high-sensitivity troponin T; DM diabetes mellitus; GDF-15 growth differentiation factor-15; HAS-BLED hypertension, abnormal renal/liver function (1 point each), stroke, bleeding history or predisposition, labile INR, elderly (.65), drugs/alcohol concomitantly (1 point each); Hb hemoglobin; Hct hematocrit; HEMORR2HAGES hepatic or renal disease, ethanol abuse, malignancy, older, reduced platelet count/function, hypertension, anemia, genetic factors, excessive fall risk, and stroke; INR international normalized ratio; NSAIDs nonsteroidal antiin ammatory drugs; ORBIT Outcomes Registry for Better Informed Treatment of Atrial Fibrillation Registry; Plt platelet count or function; SBP systolic BP. See Table 1 legend for expansion of other abbreviation.


1146 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] TABLE 3 ] Risk Factors, Risk Categories and Bleeding Events in the Validation Cohorts Risk Score Risk Factors (Score for Each Factor) Risk Categories Bleeding Events in Validation Cohort (per 100 patient-years) Low Intermediate High Low Intermediate High Agea ; biomarkersa (GDF-15 or cystatin C/CKD-EPI, cTnT-hs, and Hb); previous bleeda history (2); Y renal function (1); APT (1) Anemia (3); severe renal disease (3); age $ 75 [SBP (1); severe renal/hepatic disease (1 each); stroke (1); bleeding (1); labile INR (1); age > Hepatic/renal disease (1); ethanol abuse (1); malignancy; age > 75 y (1); YPlt (1); re-bleeding risk (2); [BP (1); anemia (1); genetic factors Shireman et al102 Age $ 70 y (0.49); female (0.31); previous bleed (0.58); recent bleed (0.62); alcohol/drug abuse Y reduced/decreased; [ elevated/increased; ABC Atrial brillation Better Care; APT antiplatelet therapy; ATRIA Anticoagulation and Risk Factors in Atrial Fibrillation; CKD-EPI Chronic Kidney Disease Epidemiology Collaboration; cTnT-hs high-sensitivity troponin T; DM diabetes mellitus; GDF-15 growth differentiation factor-15; HAS-BLED hypertension, abnormal renal/liver function (1 point each), stroke, bleeding history or predisposition, labile INR, elderly (.65), drugs/alcohol concomitantly (1 point each); Hb hemoglobin; Hct hematocrit; HEMORR2HAGES hepatic or renal disease, ethanol abuse, malignancy, older, reduced platelet count/function, hypertension, anemia, genetic factors, excessive fall risk, and stroke; INR international normalized ratio; NSAIDs nonsteroidal antiin ammatory drugs; ORBIT Outcomes Registry for Better Informed Treatment of Atrial Fibrillation Registry; Plt platelet count or function; SBP systolic BP. See Table 1 legend for expansion of other abbreviation. (Partly reproduced with permission from Zulki y et al.103 ) a Score for each variable in ABC score is based on a nonogram (see reference100 ).


(Partly reproduced with permission from Zulki y et al.103 ) a Score for each variable in ABC score is based on a nonogram (see reference100 ). b Bleeding event in original derivation cohort. c At 3 months. chestjournal.org Concomitant Medication Predisposing to Bleeding: Nonessential use of concomitant antiplatelet drugs and NSAIDs should be avoided since these medications increase the risk of bleeding in patients receiving OACs. Where concomitant antiplatelet therapy (APT) is necessary (ie, postcoronary stent implantation), the duration of combination OAC and antiplatelet drugs should be kept to the minimum.92 Since antiplatelet drugs/NSAIDs are widely available over-the-counter, patients need to be made aware of the bleeding risk associated with their use in combination with OAC. Alcohol Intake: Excessivealcoholintake(chronicorbinge- drinking) increases the risk of bleeding predominantly due to the risk of trauma, but in chronic alcohol abuse through poor medication adherence, hepatic and variceal disease. OACs should not initiated among patients consuming alcohol in excess > 14 U/week. There is no clear de nite thresholdwherebleedingriskisincreased.Patientsalsoneed to be made aware of the potential dangers associated with excessive alcohol consumption in combination with OAC/ antithrombotic therapy. Lifestyle Factors: Avoidance of work and/or leisure activities that have the potential to cause serious trauma (eg, contact sports, rock-climbing, occupations working at height or operating heavy machinery) should be advised. Bridging Periods Off Anticoagulation: Interruption of OAC should be avoided to reduce stroke risk since the majority of cardiovascular procedures (eg, pacemaker implantation or percutaneous coronary intervention [PCI]) can be safely performed on OAC. Bridging (ie, stopping OAC and providing anticoagulation cover with heparin) should be used in patients with mechanical heart valves but does not appear to be otherwise Appropriate Choice of OAC: Choice of OAC should be made on an individual basis after stroke and bleeding risk assessment and discussion with the patient.


Bridging (ie, stopping OAC and providing anticoagulation cover with heparin) should be used in patients with mechanical heart valves but does not appear to be otherwise Appropriate Choice of OAC: Choice of OAC should be made on an individual basis after stroke and bleeding risk assessment and discussion with the patient. Before an NOAC is initiated, the patient s age, body weight, and renal function should be considered to allow for appropriate dose adaptation where necessary. Falls Risk and Cognitive Impairment: In frail patients and those at high risk of falls, an individual risk assessment needs to be undertaken prior to OAC initiation. In cases where the risk is that of mechanical falls, strategies to improve walking/reduce risk of tripping should be explored (ie, walking aids, appropriate footwear, home review to remove trip hazards), whereas neurological assessment is warranted if falls are unexplained. The bene ts of ischemic stroke reduction generally outweigh the risk of harm from serious bleeding with OAC use; one estimate was that Modi able bleeding risk factors Potentially modi able bleeding risk factors Nonmodi able bleeding risk factors Biomarkers Hypertension/elevated SBP INR control (target 2.0-3.0)a ; target TTR 65% Concomitant APTs and NSAIDs Excessive alcohol intake Nonadherence to OAC/APT Avoidance of hazardous hobbies/occupations Avoidance of bridging therapy with OAC Appropriate choice of OAC and correct doseb Extreme frailty excessive falls riskc VKA management strategyd Anemia Reduced platelet count or function Renal impairment (CrCI >30 mL/min) Age (>65 y) Previous major bleeding Severe renal impairment (dialysis or renal transplant) Severe hepatic disease (cirrhosis) Malignancy Genetic factors (eg, CYP 2C9 polymorphisms) Previous stroke, small vessel disease etc Diabetes mellitus Cognitive impairment/dementia Cystatin C/CKD-EPI cTnT-hs vWF (plus other coagulation markers) Figure 2 Risk factors for bleeding with oral anticoagulation and antiplatelet therapy. a For patients receiving VKA treatment.


The bene ts of ischemic stroke reduction generally outweigh the risk of harm from serious bleeding with OAC use; one estimate was that Modi able bleeding risk factors Potentially modi able bleeding risk factors Nonmodi able bleeding risk factors Biomarkers Hypertension/elevated SBP INR control (target 2.0-3.0)a ; target TTR 65% Concomitant APTs and NSAIDs Excessive alcohol intake Nonadherence to OAC/APT Avoidance of hazardous hobbies/occupations Avoidance of bridging therapy with OAC Appropriate choice of OAC and correct doseb Extreme frailty excessive falls riskc VKA management strategyd Anemia Reduced platelet count or function Renal impairment (CrCI >30 mL/min) Age (>65 y) Previous major bleeding Severe renal impairment (dialysis or renal transplant) Severe hepatic disease (cirrhosis) Malignancy Genetic factors (eg, CYP 2C9 polymorphisms) Previous stroke, small vessel disease etc Diabetes mellitus Cognitive impairment/dementia Cystatin C/CKD-EPI cTnT-hs vWF (plus other coagulation markers) Figure 2 Risk factors for bleeding with oral anticoagulation and antiplatelet therapy. a For patients receiving VKA treatment. b Dose adaptation based on patient s age, body weight, and serum creatinine level. c Walking aids; appropriate footwear; home review to remove trip hazards; neurologic assessment where appropriate. d Increased INR monitoring, dedicated OAC clinicals, self-monitoring/self-management, educational/behavioral in- terventions. APTs antiplatelets; CKD-EPI Chronic Kidney Disease Epidemiology Collaboration; CrCl creatinine clearance; cTnT-hs high- sensitivity troponin T; CYP cytochrome P450; GDF-15 growth differentiation factor-15; INR international normalized ratio; NSAIDs nonsteroidal antiin ammatory drugs; SBP systolic blood pressure; vWF von Willebrand factor. See Figure 1 legend for expansion of other abbreviations.


APTs antiplatelets; CKD-EPI Chronic Kidney Disease Epidemiology Collaboration; CrCl creatinine clearance; cTnT-hs high- sensitivity troponin T; CYP cytochrome P450; GDF-15 growth differentiation factor-15; INR international normalized ratio; NSAIDs nonsteroidal antiin ammatory drugs; SBP systolic blood pressure; vWF von Willebrand factor. See Figure 1 legend for expansion of other abbreviations. 1148 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] the patient would need to fall 295 times per year for the risk from falls to outweigh the bene ts of stroke In patients with cognitive impairment or dementia, OAC should only be withheld if there is no available caregiver who can guarantee medication adherence. Reversal of Biochemical Anomalies: Patients with anemia or reduced platelet count or function should be treated where possible to improve their hemoglobin or platelet count. Causes of renal impairment should be investigated and where possible reversed. Patients with liver function abnormalities were generally excluded from the randomized trials, and especially where there is abnormal clotting tests, such patients may be at higher risk of bleeding on VKA, possibly less so on NOACs; in cirrhotic patients, ischemic stroke reduction may outweigh bleeding risk.96,97 Bleeding Risk Assessment: Since 2006, six risk scores have been developed and validated for the assessment of bleeding risk in AF populations.98-103 The number of risk factors included in the bleeding risk schemas varies considerably, from three100 and the score or weighting associated with each risk factor also differs Age and prior bleeding are included as risk factors in all 6 bleeding risk scores but different age cutoffs are utilized, with 3 scores employing age 75 years or to indicate greater bleeding risk.


Patients with liver function abnormalities were generally excluded from the randomized trials, and especially where there is abnormal clotting tests, such patients may be at higher risk of bleeding on VKA, possibly less so on NOACs; in cirrhotic patients, ischemic stroke reduction may outweigh bleeding risk.96,97 Bleeding Risk Assessment: Since 2006, six risk scores have been developed and validated for the assessment of bleeding risk in AF populations.98-103 The number of risk factors included in the bleeding risk schemas varies considerably, from three100 and the score or weighting associated with each risk factor also differs Age and prior bleeding are included as risk factors in all 6 bleeding risk scores but different age cutoffs are utilized, with 3 scores employing age 75 years or to indicate greater bleeding risk. Following age and prior bleeding, the most prevalent bleeding risk factors included in the scores are anemia,69,99-102 renal or uncontrolled and and prior stroke98,99 or hepatic A variety of other risk factors, including are included only in one bleeding risk score. For a comprehensive review of bleeding risk factors in AF patients see Zulki y et al.103 The bleeding risk scores range in the simplicity of calculation and the cutoffs employed to indicate low, intermediate, and high risk of bleeding, and the prevalence of bleeding events reported in the validation cohorts (Table 3).


For a comprehensive review of bleeding risk factors in AF patients see Zulki y et al.103 The bleeding risk scores range in the simplicity of calculation and the cutoffs employed to indicate low, intermediate, and high risk of bleeding, and the prevalence of bleeding events reported in the validation cohorts (Table 3). Use of Bleeding Risk Scores: As seen in Table 3, there are multiple bleeding risk scores that have been proposed for bleeding risk strati cation, with the HEMORR2HAGES (hepatic or renal disease, ethanol abuse, malignancy, older, reduced platelet count/ function, hypertension, anemia, genetic factors, excessive fall risk, and stroke), HAS-BLED (hypertension, abnormal renal/liver function [1 point each], stroke, bleeding history or predisposition, labile INR, elderly (0.65), drugs/alcohol concomitantly [1 point each]), ATRIA, ORBIT, and ABC-bleeding derived and validated in AF populations.103 The risk factors included vary by scores (Table 3), and their derivation from selected clinical trial cohorts or real- Various validation studies have been summarized in e-Table 10. Unsurprisingly, stroke risk scores are also associated with bleeding, as stroke and bleeding risks correlate with each other. For example, higher CHADS2 and CHA2DS2-VASc scores are also associated with greater bleeding risk, but the HAS-BLED score outperforms the CHADS2 and CHA2DS2-VASc scores for predicting which was also evident in the systematic review by Zhu et al.106 Composite risk scores that include stroke and bleeding end points have also been proposed but have not been shown to perform incrementally better over the individual scores.107,108 The bleeding risk scores in AF are also predictive of bleeding in non-AF populations; for example, in patients with ACS undergoing PCI-stenting.109 Adding more clinical variables marginally improves the predictive value (at least statistically), but the c-indexes still remain approximately 0.6.