Effective and less toxic reversal of low-molecular weight heparin anti- coagulation by a designer variant of protamine. J Vasc Surg. 1995;21(5):839-850. 180. Wake eld TW, Andrews PC, Wrobleski SK, et al. A [118RGD] protamine variant for nontoxic and effective reversal of conventional heparin and low-molecular-weight heparin anticoagulation. J Surg Res. 1996;63(1):280-286. 181. Dietrich CP, Shinjo SK, Moraes FA, et al. Structural fea- tures and bleeding activity of commercial low molecular weight heparins: neutralization by ATP and protamine. Semin Thromb Hemost. 1999;25(suppl 3):43-50. 182. Kuziej J, Litinas E, Hoppensteadt DA, et al. In vivo neu- tralization of unfractionated heparin and low-molecular- weight heparin by a novel salicylamide derivative. Clin Appl Thromb Hemost. 2010;16(4):377-386. 183. Monreal M, Vi as L, Monreal L, Lavin S, Lafoz E, Angles AM. Heparin-related osteoporosis in rats. A comparative study between unfractioned heparin and a low-molecular-weight heparin. Haemostasis. 1990;20(4):204-207. 184. M tzsch T, Bergqvist D, Hedner U, Nilsson B, Ostergaard P. Effects of low molecular weight heparin and unfragmented heparin on induction of osteoporosis in rats. Thromb Haemost. 1990;63(3):505-509. 185. Muir J, Hirsh J, Weitz J, Andrew M, Young E, Shaughnessy SG. A histomorphometric comparison of the effects of heparin and low-molecular-weight heparin on cancellous bone in rats. Blood. 1997;89(9):3263-3242. 186. Kock HJ, Handschin AE. Osteoblast growth inhibition by unfractionated heparin and by low molecular weight hep- arins: an in-vitro investigation. Clin Appl Thromb Hemost. 2002;8(3):251-255. 187. Folwarczna J, Janiec W, Gawor M, Pytlik M, Kaczmarczyk- Sedlak I, Nowi ska B. Effects of enoxaparin on histomor- phometric parameters of bones in rats. Pol J Pharmacol. 2004;56(4):451-457. renal function in patients on enoxaparin. J Clin Pharmacol. 2003;43(6):586-590. 156. Sanderink GJ, Guimart CG, Ozoux M-L, Jariwala NU, Shukla UA, Boutouyrie BX.


Sanderink GJ, Guimart CG, Ozoux M-L, Jariwala NU, Shukla UA, Boutouyrie BX. Pharmacokinetics and phar- macodynamics of the prophylactic dose of enoxaparin once daily over 4 days in patients with renal impairment. Thromb Res. 2002;105(3):225-231. 157. Schmid P, Brodmann D, Odermatt Y, Fischer AG, Wuillemin WA. Study of bioaccumulation of dalteparin at a therapeutic dose in patients with renal insuf ciency. J Thromb Haemost. 2009;7(10):1629-1632. 158. Mismetti P, Laporte-Simitsidis S, Navarro C, et al. Aging and venous thromboembolism in uence the pharmacody- namics of the anti-factor Xa and anti-thrombin activities of a low molecular weight heparin (nadroparin). Thromb Haemost. 1998;79(6):1162-1165. 159. Siguret V, Pautas E, F vrier M, et al. Elderly patients treated with tinzaparin (Innohep) administered once daily (175 anti-Xa IU/kg): anti-Xa and anti-IIa activities over 10 days. Thromb Haemost. 2000;84(5):800-804. 160. Lim W, Dentali F, Eikelboom JW, Crowther MA. Meta- analysis: low-molecular-weight heparin and bleeding in patients with severe renal insuf ciency. Ann Intern Med. 2006;144(9):673-684. 161. Spinler SA, Inverso SM, Cohen M, Goodman SG, Stringer KA, Antman EM; ESSENCE and TIMI 11B Investigators. Safety and ef cacy of unfractionated heparin versus enoxaparin in patients who are obese and patients with severe renal impairment: analysis from the ESSENCE and TIMI 11B studies. Am Heart J. 2003;146(1):33-41. 162. Cestac P, Bagheri H, Lapeyre-Mestre M, et al. Utilisation and safety of low molecular weight heparins: prospec- tive observational study in medical inpatients. Drug Saf. 2003;26(3):197-207. 163. Gerlach AT, Pickworth KK, Seth SK, Tanna SB, Barnes JF. Enoxaparin and bleeding complications: a review in patients with and without renal insuf ciency. Pharmacotherapy. 2000;20(7):771-775. 164. Sanderink GJ, Le Liboux A, Jariwala N, et al. The pharma- cokinetics and pharmacodynamics of enoxaparin in obese volunteers. Clin Pharmacol Ther. 2002;72(3):308-318. 165. Rabbat CG, Cook DJ, Crowther MA, et al.


2002;72(3):308-318. 165. Rabbat CG, Cook DJ, Crowther MA, et al. Dalteparin thromboprophylaxis for critically ill medical-surgical patients with renal insuf ciency. J Crit Care. 2005;20(4):357-363. 166. Douketis J, Cook D, Meade M, et al; Canadian Critical Care Trials Group. Prophylaxis against deep vein thrombosis in critically ill patients with severe renal insuf ciency with the low-molecular-weight heparin dalteparin: an assessment of safety and pharmacodynamics: the DIRECT study. Arch Intern Med. 2008;168(16):1805-1812. 167. Mah I, Aghassarian M, Drouet L, et al. Tinzaparin and enox- aparin given at prophylactic dose for eight days in medical elderly patients with impaired renal function: a comparative pharmacokinetic study. Thromb Haemost. 2007;97(4):581- 586. 168. Lindblad B, Borgstr m A, Wake eld TW, Whitehouse WM Jr, Stanley JC. Protamine reversal of anticoagulation achieved with a low molecular weight heparin. The effects on eicosanoids, clotting and complement factors. Thromb Res. 1987;48(1):31-40. 169. Massonnet-Castel S, Pelissier E, Bara L, et al. Partial rever- sal of low molecular weight heparin (PK 10169) anti-Xa activ- ity by protamine sulfate: in vitro and in vivo study during cardiac surgery with extracorporeal circulation. Haemostasis. 1986;16(2):139-146. 170. Racanelli A, Fareed J, Walenga JM, Coyne E. Biochemical and pharmacologic studies on the protamine interactions 2012 American College of Chest Physicians by Kimberly Henricks on February 10, 2012 chestjournal.chestpubs.org Downloaded from e42S Parenteral Anticoagulants 205. Warkentin TE, Maurer BT, Aster RH. Heparin-induced thrombocytopenia associated with fondaparinux. N Engl J Med. 2007;356(25):2653-2655. 206. Warkentin TE, Cook RJ, Marder VJ, et al. Anti-platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin. Blood. 2005;106(12):3791-3796. 207. Kuo KH, Kovacs MJ. Fondaparinux: a potential new therapy for HIT. Hematology. 2005;10(4):271-275. 208. Blackmer AB, Oertel MD, Valgus JM. Fondaparinux and the management of heparin-induced thrombocytopenia: the journey continues. Ann Pharmacother. 2009;43(10):1636-1646. 209.


Fondaparinux and the management of heparin-induced thrombocytopenia: the journey continues. Ann Pharmacother. 2009;43(10):1636-1646. 209. Parody R, Oliver A, Souto JC, Fontcuberta J. Fondaparinux (ARIXTRA) as an alternative anti-thrombotic prophylaxis when there is hypersensitivity to low molecular weight and unfractionated heparins. Haematologica. 2003;88(11): ECR32. 210. Matziolis G, Perka C, Disch A, Zippel H. Effects of fonda- parinux compared with dalteparin, enoxaparin and unfrac- tionated heparin on human osteoblasts. Calcif Tissue Int. 2003;73(4):370-379. 211. Handschin AE, Trentz OA, Hoerstrup SP, Kock HJ, Wanner GA, Trentz O. Effect of low molecular weight hep- arin (dalteparin) and fondaparinux (Arixtra) on human oste- oblasts in vitro. Br J Surg. 2005;92(2):177-183. 212. Lagrange F, Vergnes C, Brun JL, et al. Absence of placental transfer of pentasaccharide (Fondaparinux, Arixtra) in the dually perfused human cotyledon in vitro. Thromb Haemost. 2002;87(5):831-835. 213. Demp e CE. Minor transplacental passage of fondaparinux in vivo. N Engl J Med. 2004;350(18):1914-1915. 214. Toschi V, Lettino M, Gallo R, Badimon JJ, Chesebro JH. Biochemistry and biology of hirudin. Coron Artery Dis. 1996;7(6):420-428. 215. Wallis RB. Hirudins: from leeches to man. Semin Thromb Hemost. 1996;22(2):185-196. 216. Lef vre G, Duval M, Gauron S, et al. Effect of renal impairment on the pharmacokinetics and pharmacodynamics of desirudin. Clin Pharmacol Ther. 1997;62(1):50-59. 217. Tardy B, Lecompte T, Boelhen F, et al; GEHT-HIT Study Group. Predictive factors for thrombosis and major bleed- ing in an observational study in 181 patients with heparin- induced thrombocytopenia treated with lepirudin. Blood. 2006;108(5):1492-1496. 218. Maraganore JM, Bourdon P, Jablonski J, Ramachandran KL, Fenton JW II. Design and characterization of hirulogs: a novel class of bivalent peptide inhibitors of thrombin. Biochemistry. 1990;29(30):7095-7101. 219. Skrzypczak-Jankun E, Carperos VE, Ravichandran KG, Tulinsky A, Westbrook M, Maraganore JM. Structure of the hirugen and hirulog 1 complexes of alpha-thrombin. J Mol Biol. 1991;221(4):1379-1393. 220.


Structure of the hirugen and hirulog 1 complexes of alpha-thrombin. J Mol Biol. 1991;221(4):1379-1393. 220. Witting JI, Bourdon P, Maraganore JM, Fenton JW II. Hirulog-1 and -B2 thrombin speci city. Biochem J. 1992;287(pt 2):663-664. 221. Fox I, Dawson A, Loynds P, et al. Anticoagulant activity of Hirulog, a direct thrombin inhibitor, in humans. Thromb Haemost. 1993;69(2):157-163. 222. Robson R. The use of bivalirudin in patients with renal impairment. J Invasive Cardiol. 2000;12(suppl F):33F-6. 223. White HD. Pharmacological and clinical pro le of biva- lirudin in the treatment of patients with acute coronary syndrome. Expert Opin Drug Metab Toxicol. 2009;5(5): 529-538. 224. Banner DW, Hadv ry P. Inhibitor binding to thrombin: x-ray crystallographic studies. Adv Exp Med Biol. 1993;340: 27-33. 188. Casele HL, Laifer SA. Prospective evaluation of bone den- sity in pregnant women receiving the low molecular weight heparin enoxaparin sodium. J Matern Fetal Med. 2000;9(2): 122-125. 189. Pettil V, Leinonen P, Markkola A, Hiilesmaa V, Kaaja R. Postpartum bone mineral density in women treated for thromboprophylaxis with unfractionated heparin or LMW heparin. Thromb Haemost. 2002;87(2):182-186. 190. Wawrzysnka L, Tomkowski WZ, Przedlacki J, Hajduk B, Torbicki A. Changes in bone density during long-term administration of low-molecular-weight heparins or aceno- coumarol for secondary prophylaxis of venous thrombo- embolism. Pathophysiol Haemost Thromb. 2003;33(2): 64-67. 191. Lefkou E, Khamashta M, Hampson G, Hunt BJ. Review: Low-molecular-weight heparin-induced osteoporosis and osteoporotic fractures: a myth or an existing entity? Lupus. 2010;19(1):3-12. 192. Choay J, Lormeau JC, Petitou M, Sina P, Fareed J. Struc- tural studies on a biologically active hexasaccharide obtained from heparin. Ann N Y Acad Sci. 1981;370:644-649. 193. Thunberg L, B ckstr m G, Lindahl U. Further character- ization of the antithrombin-binding sequence in heparin. Carbohydr Res. 1982;100:393-410. 194. Choay J. Biologic studies on chemically synthesized penta- saccharide and tetrasaccharide fragments.


Choay J. Biologic studies on chemically synthesized penta- saccharide and tetrasaccharide fragments. Semin Thromb Hemost. 1985;11(2):81-85. 195. Atha DH, Lormeau JC, Petitou M, Rosenberg RD, Choay J. Contribution of 3-O- and 6-O-sulfated glucosamine residues in the heparin-induced conformational change in antithrombin III. Biochemistry. 1987;26(20):6454-6461. 196. Depasse F, Gilbert M, Goret V, Rolland N, Samama MM. Anti-Xamonitoring:inter-assayvariability.ThrombHaemost. 2000;84(6):1122-1123. 197. Kitchen S, Iampietro R, Woolley AM, Preston FE. Anti Xa monitoring during treatment with low molecular weight heparin or danaparoid: inter-assay variability. Thromb Haemost. 1999;82(4):1289-1293. 198. Boneu B, Necciari J, Cariou R, et al. Pharmacokinetics and tolerance of the natural pentasaccharide (SR90107/ Org31540) with high af nity to antithrombin III in man. Thromb Haemost. 1995;74(6):1468-1473. 199. Donat F, Duret JP, Santoni A, et al. The pharmacoki- netics of fondaparinux sodium in healthy volunteers. Clin Pharmacokinet. 2002;41(suppl 2):1-9. 200. Lieu C, Shi J, Donat F, et al. Fondaparinux sodium is not metabolised in mammalian liver fractions and does not inhibit cytochrome P450-mediated metabolism of con- comitant drugs. Clin Pharmacokinet. 2002;41(suppl 2): 19-26. 201. Paolucci F, Clavi s MC, Donat F, Necciari J. Fondaparinux sodium mechanism of action: identi cation of speci c binding to puri ed and human plasma-derived proteins. Clin Pharmacokinet. 2002;41(suppl 2):11-18. 202. Bijsterveld NR, Moons AH, Boekholdt SM, et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation. 2002;106(20):2550-2554. 203. Savi P, Chong BH, Greinacher A, et al. Effect of fonda- parinux on platelet activation in the presence of heparin- dependent antibodies: a blinded comparative multicenter study with unfractionated heparin. Blood. 2005;105(1): 139-144. 204. Rota E, Bazzan M, Fantino G. Fondaparinux-related throm- bocytopenia in a previous low-molecular-weight heparin (LMWH)-induced heparin-induced thrombocytopenia (HIT). Thromb Haemost. 2008;99(4):779-781.


Rota E, Bazzan M, Fantino G. Fondaparinux-related throm- bocytopenia in a previous low-molecular-weight heparin (LMWH)-induced heparin-induced thrombocytopenia (HIT). Thromb Haemost. 2008;99(4):779-781. 2012 American College of Chest Physicians by Kimberly Henricks on February 10, 2012 chestjournal.chestpubs.org Downloaded from www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e43S ratio in patients transitioning from argatroban to warfarin. Pharmacotherapy. 2005;25(2):157-164. 229. Bartholomew J. Transition to an oral anticoagulant in patients with heparin-induced thrombocytopenia. Chest. 2005;127(suppl 2):27S-34S. 230. Hursting MJ, Lewis BE, Macfarlane DE. Transitioning from argatroban to warfarin therapy in patients with hepa- rin-induced thrombocytopenia. Clin Appl Thromb Hemost. 2005;11(3):279-287. 231. S rensen B, Ingerslev J. A direct thrombin inhibitor stud- ied by dynamic whole blood clot formation. Haemostatic response to ex-vivo addition of recombinant factor VIIa or activated prothrombin complex concentrate. Thromb Haemost. 2006;96(4):446-453. 225. Hursting MJ, Alford KL, Becker JC, et al. Novastan (brand of argatroban): a small-molecule, direct thrombin inhibitor. Semin Thromb Hemost. 1997;23(6):503-516. 226. Swan SK, Hursting MJ. The pharmacokinetics and phar- macodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction. Pharmacotherapy. 2000;20(3): 318-329. 227. Warkentin TE, Greinacher A, Craven S, Dewar L, Sheppard JA, Ofosu FA. Differences in the clinically effec- tive molar concentrations of four direct thrombin inhibi- tors explain their variable prothrombin time prolongation. Thromb Haemost. 2005;94(5):958-964. 228. Arpino PA, Demirjian Z, Van Cott EM. Use of the chromo- genic factor X assay to predict the international normalized 2012 American College of Chest Physicians by Kimberly Henricks on February 10, 2012 chestjournal.chestpubs.org Downloaded from


*Writing group members are required to recuse themselves from voting on sections to which their specific relationships with industry may apply; see Appendix 1 for detailed information. HRS Representative. ACC/AHA Task Force on Clinical Practice Guidelines Liaison. STS Representative. ACC/AHA Representative. ACC/AHA Task Force on Performance Measures Representative. The American Heart Association requests that this document be cited as follows: January CT, Wann LS, Calkins H, Chen LY, Cigarroa JE, Cleveland JC Jr, Ellinor PT, Ezekowitz MD, Field ME, Furie KL, Heidenreich PA, Murray KT, Shea JB, Tracy CM, Yancy CW. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation. 2019;140:e125 2019 by the American Heart Association, Inc., the American College of Cardiology Foundation, and the Heart Rhythm Society.


2019;140:e125 2019 by the American Heart Association, Inc., the American College of Cardiology Foundation, and the Heart Rhythm Society. ACC/AHA/HRS GUIDELINE 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society Circulation https://www.ahajournals.org/journal/circ ACC/AHA Task Force Members, see page e142 Key Words: AHA Scientific Statements focused update acute coronary syndrome anticoagulants anticoagulation agents antiplatelet agents apixaban atrial fibrillation atrial flutter cardioversion coronary artery disease coronary heart disease stents dabigatran edoxaban hypertension idarucizumab myocardial infarction obesity percutaneous coronary intervention risk factors rivaroxaban sleep apnea stroke thromboembolism warfarin WRITING GROUP MEMBERS* Craig T. January, MD, PhD, FACC, Chair L. Samuel Wann, MD, MACC, FAHA, Vice Chair Hugh Calkins, MD, FACC, FAHA, FHRS* Lin Y. Chen, MD, MS, FACC, FAHA, FHRS Joaquin E. Cigarroa, MD, FACC Joseph C. Cleveland Jr, MD, FACC* Patrick T. Ellinor, MD, PhD* Michael D. Ezekowitz, MBChB, DPhil, FACC, FAHA* Michael E. Field, MD, FACC, FAHA, FHRS Karen L. Furie, MD, MPH, FAHA Paul A. Heidenreich, MD, FACC, FAHA Katherine T. Murray, MD, FACC, FAHA, FHRS Julie B. Shea, MS, RNCS, FHRS* Cynthia M. Tracy, MD, FAHA Clyde W. Yancy, MD, MACC, FAHA Developed in Collaboration With the Society of Thoracic Surgeons CLINICAL STATEMENTS AND GUIDELINES TABLE OF CONTENTS Preamble (Full Version) e126 1. Introduction e128 1.1. Methodology and Evidence Review e129 1.2. Organization of the Writing Group e129 1.3. Document Review and Approval e129 1.4. Abbreviations e129 4. Prevention of Thromboembolism e130 4.1. Risk-Based Anticoagulant Therapy (Modified From Section 4.1., Risk-Based Antithrombotic Therapy, in the 2014 AF Guideline) e130 4.1.1.


Risk-Based Anticoagulant Therapy (Modified From Section 4.1., Risk-Based Antithrombotic Therapy, in the 2014 AF Guideline) e130 4.1.1. Selecting an Anticoagulant Regimen Balancing Risks and Benefits (Modified From Section 4.1.1., Selecting an Antithrombotic Regimen Balancing Risks and Benefits, in the 2014 AF Guideline) e130 4.2. Anticoagulant Options (Modified From Section 4.2., Antithrombotic Options, in the 2014 AF Guideline) e134 4.3. Interruption and Bridging Anticoagulation e134 4.4. Nonpharmacological Stroke Prevention e135 4.4.1. Percutaneous Approaches to Occlude the LAA e135 4.4.2. Cardiac Surgery LAA Occlusion/ Excision e136 6. Rhythm Control e136 6.1. Electrical and Pharmacological Cardioversion of AF and Atrial Flutter e136 6.1.1. Prevention of Thromboembolism e136 6.3. AF Catheter Ablation to Maintain Sinus Rhythm e138 6.3.4. Catheter Ablation in HF e138 7. Specific Patient Groups and AF e138 7.4. AF Complicating ACS e138 7.12. Device Detection of AF and Atrial Flutter (New) e141 7.13. Weight Loss (New) e142 References e143 Appendix 1: Author Relationships With Industry and Other Entities (Relevant) e148 Appendix 2: Abbreviated Reviewer Relationships With Industry and Other Entities e150 PREAMBLE (FULL VERSION) Since 1980, the American College of Cardiology (ACC) and American Heart Association (AHA) have translated scientific evidence into clinical practice guidelines with recommendations to improve cardiovascular health. These guidelines, which are based on systematic meth- ods to evaluate and classify evidence, provide a founda- tion for the delivery of quality cardiovascular care. The ACC and AHA sponsor the development and publica- tion of clinical practice guidelines without commercial support, and members volunteer their time to the writ- ing and review efforts. Guidelines are official policy of the ACC and AHA. For some guidelines, the ACC and AHA partner with other organizations.


For some guidelines, the ACC and AHA partner with other organizations. This guideline is a collaboration of the ACC and AHA with the Heart Rhythm Society (HRS) as a partner and the Society of Thoracic Surgeons as a collaborator. Intended Use Clinical practice guidelines provide recommendations applicable to patients with or at risk of developing car- diovascular disease. The focus is on medical practice in the United States, but these guidelines are relevant to patients throughout the world. Although guidelines may be used to inform regulatory or payer decisions, the intent is to improve quality of care and align with patients interests. Guidelines are intended to define practices meeting the needs of patients in most, but not all, circumstances, and should not replace clinical judgment. Clinical Implementation Management, in accordance with guideline recom- mendations, is effective only when followed by both practitioners and patients. Adherence to recommen- dations can be enhanced by shared decision-making between clinicians and patients, with patient engage- ment in selecting interventions on the basis of individ- ual values, preferences, and associated conditions and comorbidities. Methodology and Modernization The ACC/AHA Task Force on Clinical Practice Guidelines (Task Force) continuously reviews, updates, and modi- fies guideline methodology on the basis of published standards from organizations, including the Institute and on the basis of internal reevalu- ation. Similarly, presentation and delivery of guidelines are reevaluated and modified in response to evolving technologies and other factors to optimally facilitate dissemination of information to healthcare profession- als at the point of care. Beginning in 2017, numerous modifications to the guidelines have been and continue to be implemented to make guidelines shorter and enhance user friendli- ness.


Beginning in 2017, numerous modifications to the guidelines have been and continue to be implemented to make guidelines shorter and enhance user friendli- ness. Guidelines are written and presented in a modu- lar knowledge chunk format, in which each chunk in- cludes a table of recommendations, a brief synopsis, recommendation-specific supportive text and, when appropriate, flow diagrams or additional tables. Hyper- linked references are provided for each modular knowl- edge chunk to facilitate quick access and review. More CLINICAL STATEMENTS AND GUIDELINES structured guidelines including word limits ( targets ) and a web guideline supplement for useful but non- critical tables and figures are 2 such changes. Also, to promote conciseness, the Preamble is presented in ab- breviated form in the executive summary and full-text guideline documents. In recognition of the importance of cost value con- siderations in certain guidelines, when appropriate and feasible, an analysis of value for a drug, device, or in- tervention may be performed in accordance with the To ensure that guideline recommendations remain current, new data are reviewed on an ongoing basis, with full guideline revisions commissioned ideally in ap- proximate 6-year cycles. Publication of potentially prac- tice-changing new study results relevant to an existing or new drug, device, or management strategy prompts evaluation by the Task Force, in consultation with the relevant guideline writing committee, to determine whether a focused update should be commissioned.


Publication of potentially prac- tice-changing new study results relevant to an existing or new drug, device, or management strategy prompts evaluation by the Task Force, in consultation with the relevant guideline writing committee, to determine whether a focused update should be commissioned. For additional information and policies on guideline de- velopment, we encourage readers to consult the ACC/ AHA guideline methodology manualP-4 and other meth- Selection of Writing Committee Members The Task Force strives to ensure that the guideline writing committee both contains requisite expertise and is representative of the broader medical commu- nity by selecting experts from a broad array of back- grounds, representing different geographic regions, sexes, races, ethnicities, intellectual perspectives/bi- ases, and scopes of clinical practice, and by inviting organizations and professional societies with related interests and expertise to participate as partners or collaborators. Relationships With Industry and Other Entities The ACC and AHA have rigorous policies and meth- ods to ensure that documents are developed without bias or improper influence. The complete policy on relationships with industry and other entities (RWI) can be found online. Appendix 1 of the guideline lists writing committee members relevant RWI; for the purposes of full transparency, their comprehensive disclosure information is available online. Compre- hensive disclosure information for the Task Force is also available online. Evidence Review and Evidence Review Committees In developing recommendations, the writing commit- tee uses evidence-based methodologies that are based on all available data.P-4 P-6 Literature searches focus on randomized controlled trials (RCTs) but also include registries, nonrandomized comparative and descriptive studies, case series, cohort studies, systematic reviews, and expert opinion. Only key references are cited.


Evidence Review and Evidence Review Committees In developing recommendations, the writing commit- tee uses evidence-based methodologies that are based on all available data.P-4 P-6 Literature searches focus on randomized controlled trials (RCTs) but also include registries, nonrandomized comparative and descriptive studies, case series, cohort studies, systematic reviews, and expert opinion. Only key references are cited. An independent evidence review committee is commissioned when there are one or more questions deemed of utmost clinical importance that merit formal systematic review to determine which patients are most likely to benefit from a drug, device, or treatment strat- egy, and to what degree. Criteria for commissioning an evidence review committee and formal systematic re- view include absence of a current authoritative system- atic review, feasibility of defining the benefit and risk in a timeframe consistent with the writing of a guide- line, relevance to a substantial number of patients, and likelihood that the findings can be translated into ac- tionable recommendations. Evidence review committee members may include methodologists, epidemiologists, clinicians, and biostatisticians. Recommendations de- veloped by the writing committee on the basis of the systematic review are marked SR . Guideline-Directed Management and Therapy The term guideline-directed management and therapy encompasses clinical evaluation, diagnostic testing, and both pharmacological and procedural treatments. For these and all recommended drug treatment regimens, the reader should confirm dosage with product insert material and evaluate for contraindications and interactions. Rec- ommendations are limited to drugs, devices, and treat- ments approved for clinical use in the United States. Class of Recommendation and Level of Evidence The Class of Recommendation (COR) indicates the strength of recommendation, encompassing the esti- mated magnitude and certainty of benefit in proportion to risk.


Class of Recommendation and Level of Evidence The Class of Recommendation (COR) indicates the strength of recommendation, encompassing the esti- mated magnitude and certainty of benefit in proportion to risk. The Level of Evidence (LOE) rates the quality of scientific evidence supporting the intervention on the basis of the type, quantity, and consistency of data from clinical trials and other sources (Table 1).P-5 Glenn N. Levine, MD, FACC, FAHA Chair, ACC/AHA Task Force on Clinical Practice Guidelines CLINICAL STATEMENTS AND GUIDELINES The purpose of this document is to update the 2014 AHA/ACC/HRS Guideline for the Management of Pa- tients With Atrial Fibrillation S1.3-1 (2014 AF Guideline) in areas for which new evidence has emerged since its publication. The scope of this focused update of the 2014 AF Guideline includes revisions to the section on anticoagulation (because of the approval of new med- ications and thromboembolism protection devices), revisions to the section on catheter ablation of atrial fibrillation (AF), revisions to the section on the man- agement of AF complicating acute coronary syndrome (ACS), and new sections on device detection of AF and weight loss. The areas of the 2014 AF Guideline that were updated were limited to those for which impor- tant new data from clinical trials had emerged and/ or new US Food and Drug Administration (FDA) indi- cations for thromboembolism protection devices have appeared in the data available to the writing group up to August 2018. All recommendations (new, modified, and un- changed) for each updated clinical section are included to provide a comprehensive assessment. The text ex- Table 1.


All recommendations (new, modified, and un- changed) for each updated clinical section are included to provide a comprehensive assessment. The text ex- Table 1. Applying Class of Recommendation and Level of Evidence to Clinical Strategies, Interventions, Treatments, or Diagnostic Testing in Patient Care* (Updated August 2015) CLINICAL STATEMENTS AND GUIDELINES plains new and modified recommendations, whereas recommendations from the previous guideline that have been deleted or superseded no longer appear. Please consult the full-text version of the 2014 AF for text and evidence tables supporting the unchanged recommendations and for clinical ar- eas not addressed in this focused update. Individual recommendations in this focused update will be incor- porated into the full-text guideline in the future. Rec- ommendations from the prior guideline that remain current have been included for completeness, but the LOE reflects the COR/LOE system used when initially developed. New and modified recommendations in this focused update reflect the latest COR/LOE system, in which LOE B and C are subcategorized for greater The section numbers correspond to the full-text guideline sections. 1.1. Methodology and Evidence Review Clinical trials presented at the annual scientific meet- ings of the ACC, AHA, Heart Rhythm Society (HRS), and European Society of Cardiology, as well as other selected data published in a peer-reviewed format through August 2018, were reviewed by the Task Force and members of the 2014 AF Guideline writ- ing group to identify trials and other key data that might affect guideline recommendations. The infor- mation considered important enough to prompt up- dated recommendations is included in evidence tables in the Online Data Supplement. The complete section of recommendations (new, modified, and unchanged) for each clinical section is included to provide a com- prehensive overview for the reader. Recommendations that have been deleted or superseded are not incor- porated.


Recommendations that have been deleted or superseded are not incor- porated. The text supporting the new and modified recommendations is provided. After the preliminary recommendation and text were drafted for percutaneous approaches to occlusion of the left atrial appendage (LAA), it was appreciated that the primary author of the section had, by strict cri- teria, an RWI relevant to the section. Task Force and organizational leadership directed that both the rec- ommendation and text be discarded and the section be constructed de novo by both a new primary author and new primary reviewer, both without RWI. This new section was thoroughly reviewed by the entire writing group, and the de novo formulated recommendation, as with all recommendations in the focused update, was formally voted on by the writing group. 1.2. Organization of the Writing Group For this focused update, representative members of the 2014 AF writing committee were invited to participate, and they were joined by additional invited members to form a new writing group, referred to as the 2018 AF Guideline Focused Update Writing Group. Members were required to disclose all RWI relevant to the data un- der consideration. The group was composed of clinicians with broad expertise related to AF and its treatment, in- cluding the areas of adult cardiology, electrophysiology, cardiothoracic surgery, and heart failure (HF). The writ- ing group included representatives from the ACC, AHA, HRS, and the Society of Thoracic Surgeons. 1.3. Document Review and Approval The focused update was reviewed by 2 official re- viewers each nominated by the ACC, AHA, and HRS; 1 AHA/ACC lay reviewer; 1 organizational reviewer from the Society of Thoracic Surgeons; and 29 in- dividual content reviewers. Reviewers abbreviated RWI information is published in this document (Ap- pendix 2), and their detailed disclosures are available online.


Reviewers abbreviated RWI information is published in this document (Ap- pendix 2), and their detailed disclosures are available online. This document was approved for publication by the governing bodies of the ACC, AHA, and HRS and was endorsed by the Society of Thoracic Surgeons. Abbreviation Meaning/Phrase ACS acute coronary syndrome AF atrial fibrillation AHRE atrial high-rate episodes congestive heart failure, hypertension, age >75 years, diabetes mellitus, stroke/transient ischemia attack/ thromboembolism -VASc congestive heart failure, hypertension, age 75 years (doubled), diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism (doubled), vascular disease, age 65 to 74 years, sex category CI confidence interval CKD chronic kidney disease CMS US Centers for Medicare & Medicaid Services CrCl creatinine clearance DAPT dual-antiplatelet therapy FDA US Food and Drug Administration HF heart failure HFrEF heart failure with reduced left ventricular ejection fraction HR hazard ratio INR international normalized ratio LAA left atrial appendage LV left ventricular MI myocardial infarction NOAC non vitamin K oral anticoagulant PCI percutaneous coronary intervention RCT randomized controlled trial TIMI Thrombolysis in Myocardial Infarction CLINICAL STATEMENTS AND GUIDELINES 4. PREVENTION OF THROMBOEMBOLISM 4.1. Risk-Based Anticoagulant Therapy (Modified From Section 4.1., Risk-Based Antithrombotic Therapy, in the 2014 AF Guideline) 4.1.1. Selecting an Anticoagulant Regimen Balancing Risks and Benefits (Modified From Section 4.1.1., Selecting an Antithrombotic Regimen Balancing Risks and Benefits, in the 2014 AF Guideline) Introductory Text The distinction between nonvalvular and valvular AF has confused clinicians, varying among AF clinical tri- als of non vitamin K oral anticoagulants (NOACs) (ie, dabigatran [a direct thrombin inhibitor] and rivaroxa- ban, apixaban, and edoxaban [factor Xa inhibitors]; also referred to as direct-acting oral anticoagulants [DOACs]) and between North American and Europe- an AF guidelines.


Selecting an Anticoagulant Regimen Balancing Risks and Benefits (Modified From Section 4.1.1., Selecting an Antithrombotic Regimen Balancing Risks and Benefits, in the 2014 AF Guideline) Introductory Text The distinction between nonvalvular and valvular AF has confused clinicians, varying among AF clinical tri- als of non vitamin K oral anticoagulants (NOACs) (ie, dabigatran [a direct thrombin inhibitor] and rivaroxa- ban, apixaban, and edoxaban [factor Xa inhibitors]; also referred to as direct-acting oral anticoagulants [DOACs]) and between North American and Europe- an AF guidelines. Valvular AF generally refers to AF in the setting of moderate-to-severe mitral stenosis (potentially requiring surgical intervention) or in the presence of an artificial (mechanical) heart valve. Val- vular AF is considered an indication for long-term anticoagulation with warfarin. In contrast, nonvalvu- lar AF does not imply the absence of valvular heart disease. Instead, as used in the present focused up- date, nonvalvular AF is AF in the absence of mod- erate-to-severe mitral stenosis or a mechanical heart valve. This is because in most AF NOAC clinical trials, up to approximately 20% of patients were enrolled with various valvular defects, including mild mitral stenosis, mitral regurgitation, aortic stenosis, aortic regurgitation, and tricuspid regurgitation;S4.1.1-1,S4.1.1-2 some trials enrolled small numbers of patients with valve repair, valvuloplasty, and bioprosthetic valves. Furthermore, meta-analysis derived data from the original clinical trials suggest that, among patients with AF and these valvular lesions and operations, NOACs reduce stroke and systemic embolism com- pared with warfarin, but with differences in bleed- For recommendations from the 2014 AF guideline that were modified only to define the exclusion criteria for valvular AF or to change anti- thrombotic to anticoagulant, LOE and supportive text have not been updated. A fifth NOAC, betrixa- ban, has not been approved by the FDA for use in patients with AF.


A fifth NOAC, betrixa- ban, has not been approved by the FDA for use in patients with AF. Antithrombotic (anticoagulant com- bined with antiplatelet) therapy is discussed in Sec- Recommendations for Selecting an Anticoagulant Regimen Balancing Risks and Benefits Referenced studies that support new or modified recommendations are summarized in Online Data Supplements 1 and 2. COR LOE Recommendations I A For patients with AF and an elevated -VASc score of 2 or greater in men or 3 or greater in women, oral anticoagulants are recommended. Options include: Warfarin (LOE: A)S4.1.1-5 S4.1.1-7 Dabigatran (LOE: B)S4.1.1-8 Rivaroxaban (LOE: B)S4.1.1-9 Apixaban (LOE: B),S4.1.1-10 or Edoxaban (LOE: B-R)S4.1.1-11 MODIFIED: This recommendation has been updated in response to the approval of edoxaban, a new factor Xa inhibitor. More precision in the use of CHA2 -VASc scores is specified in subsequent recommendations. The LOEs for warfarin, dabigatran, rivaroxaban, and apixaban have not been updated for greater granularity as per the new LOE system. (Section 4.1. in the 2014 AF Guideline) The original text can be found in Section 4.1 of the 2014 AF guideline. Additional information about the comparative effectiveness and bleeding risk of NOACs can be found in Section 4.2.2.2. B B B B-R I A NOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) are recommended over warfarin in NOAC-eligible patients with AF (except with moderate-to-severe mitral stenosis or a mechanical heart NEW: Exclusion criteria are now defined as moderate-to-severe mitral stenosis or a mechanical heart valve. When the NOAC trials are considered as a group, the direct thrombin inhibitor and factor Xa inhibitors were at least noninferior and, in some trials, superior to warfarin for preventing stroke and systemic embolism and were associated with lower risks of serious bleeding.


When the NOAC trials are considered as a group, the direct thrombin inhibitor and factor Xa inhibitors were at least noninferior and, in some trials, superior to warfarin for preventing stroke and systemic embolism and were associated with lower risks of serious bleeding. I A Among patients treated with warfarin, the international normalized ratio (INR) should be determined at least weekly during initiation of anticoagulant therapy and at least monthly when anticoagulation (INR in range) is stable.S4.1.1-12 S4.1.1-14 MODIFIED: Antithrombotic was changed to anticoagulant. I B In patients with AF (except with moderate- to-severe mitral stenosis or a mechanical heart valve), the CHA2 -VASc score is recommended for assessment of stroke MODIFIED: Exclusion criteria are now defined as moderate-to-severe mitral stenosis or a mechanical heart valve. Patients with AF with bioprosthetic heart valves are addressed in the supportive text. (Section 4.1. in the 2014 AF guideline) I B For patients with AF who have mechanical heart valves, warfarin is MODIFIED: New information is included in the supportive text. CLINICAL STATEMENTS AND GUIDELINES I B Selection of anticoagulant therapy should be based on the risk of thromboembolism, irrespective of whether the AF pattern is paroxysmal, persistent, or MODIFIED: Antithrombotic was changed to anticoagulant. I B-NR Renal function and hepatic function should be evaluated before initiation of a NOAC and should be reevaluated at least MODIFIED: Evaluation of hepatic function was added. LOE was updated from B to B-NR. New evidence was added. (Section 4.1. in the 2014 AF Guideline) I C In patients with AF, anticoagulant therapy should be individualized on the basis of shared decision-making after discussion of the absolute risks and relative risks of stroke and bleeding, as well as the patient s values and preferences. MODIFIED: Antithrombotic was changed to anticoagulant.


(Section 4.1. in the 2014 AF Guideline) I C In patients with AF, anticoagulant therapy should be individualized on the basis of shared decision-making after discussion of the absolute risks and relative risks of stroke and bleeding, as well as the patient s values and preferences. MODIFIED: Antithrombotic was changed to anticoagulant. I C For patients with atrial flutter, anticoagulant therapy is recommended according to the same risk profile used for AF. MODIFIED: Antithrombotic was changed to anticoagulant. I C Reevaluation of the need for and choice of anticoagulant therapy at periodic intervals is recommended to reassess stroke and bleeding risks. MODIFIED: Antithrombotic was changed to anticoagulant. I C-EO For patients with AF (except with moderate-to-severe mitral stenosis or a mechanical heart valve) who are unable to maintain a therapeutic INR level with warfarin, use of a NOAC is recommended. MODIFIED: Exclusion criteria are now defined as moderate-to-severe mitral stenosis or a mechanical heart valve, and this recommendation has been changed in response to the approval of edoxaban. (Section 4.1. in the 2014 AF Guideline) IIa B For patients with AF (except with moderate- to-severe mitral stenosis or a mechanical heart valve) and a CHA2 -VASc score of 0 in men or 1 in women, it is reasonable to omit anticoagulant therapy.S4.1.1-24,S4.1.1-25 MODIFIED: Exclusion criteria are now defined as moderate-to-severe mitral stenosis or a mechanical heart valve. (Section 4.1. in the 2014 AF Guideline) IIb B-NR For patients with AF who have a CHA2 - VASc score of 2 or greater in men or 3 or greater in women and who have end-stage chronic kidney disease (CKD; creatinine clearance [CrCl] <15 mL/min) or are on dialysis, it might be reasonable to prescribe warfarin (INR 2.0 to 3.0) or apixaban for MODIFIED: New evidence has been added.


(Section 4.1. in the 2014 AF Guideline) IIb B-NR For patients with AF who have a CHA2 - VASc score of 2 or greater in men or 3 or greater in women and who have end-stage chronic kidney disease (CKD; creatinine clearance [CrCl] <15 mL/min) or are on dialysis, it might be reasonable to prescribe warfarin (INR 2.0 to 3.0) or apixaban for MODIFIED: New evidence has been added. LOE was updated from B to B-NR. (Section 4.1. in the 2014 AF Guideline) IIb B-R For patients with AF (except with moderate- to-severe mitral stenosis or a mechanical heart valve) and moderate-to-severe CKD (serum creatinine 1.5 mg/dL [apixaban], CrCl 15 to 30 mL/min [dabigatran], CrCl 50 mL/min [rivaroxaban], or CrCl 15 to 50 mL/ min [edoxaban]) with an elevated CHA2 - VASc score, treatment with reduced doses of direct thrombin or factor Xa inhibitors may be considered (eg, dabigatran, rivaroxaban, apixaban, or edoxaban).S4.1.1-11 MODIFIED: Exclusion criteria are now defined as moderate-to-severe mitral stenosis or a mechanical heart valve, and this recommendation has been changed in response to the approval of edoxaban. LOE was updated from C to B-R. (Section 4.1. in the 2014 AF Guideline) IIb C- LD For patients with AF (except with moderate- to-severe mitral stenosis or a mechanical heart valve) and a CHA2 -VASc score of 1 in men and 2 in women, prescribing an oral anticoagulant to reduce thromboembolic stroke risk may be considered.S4.1.1-31 S4.1.1-35 MODIFIED: Exclusion criteria are now defined as moderate-to-severe mitral stenosis or a mechanical heart valve, and evidence was added to support separate risk scores by sex. LOE was updated from C to C-LD.


LOE was updated from C to B-R. (Section 4.1. in the 2014 AF Guideline) IIb C- LD For patients with AF (except with moderate- to-severe mitral stenosis or a mechanical heart valve) and a CHA2 -VASc score of 1 in men and 2 in women, prescribing an oral anticoagulant to reduce thromboembolic stroke risk may be considered.S4.1.1-31 S4.1.1-35 MODIFIED: Exclusion criteria are now defined as moderate-to-severe mitral stenosis or a mechanical heart valve, and evidence was added to support separate risk scores by sex. LOE was updated from C to C-LD. (Section 4.1. in the 2014 AF Guideline) III: No Benefit C-EO In patients with AF and end-stage CKD or on dialysis, the direct thrombin inhibitor dabigatran or the factor Xa inhibitors rivaroxaban or edoxaban are not recommended because of the lack of evidence from clinical trials that benefit MODIFIED: New data have been included. Edoxaban received FDA approval and has been added to the recommendation. LOE was updated from C to C-EO. (Section 4.1. in the 2014 AF Guideline) III: Harm B-R The direct thrombin inhibitor dabigatran should not be used in patients with AF and a mechanical heart valve.S4.1.1-39 MODIFIED: Evidence was added. LOE was updated from B to B-R. Other NOACs are addressed in the supportive text. (Section 4.1. in the 2014 AF Guideline) Recommendation-Specific Supportive Text (New or Modified) 1. New data are available for edoxaban.


(Section 4.1. in the 2014 AF Guideline) Recommendation-Specific Supportive Text (New or Modified) 1. New data are available for edoxaban. Edoxaban (30 or 60 mg once daily) was studied in a large ran- domized prospective AF trial; it was found to be noninferior to warfarin with regard to the preven- tion of stroke or systemic embolization and was associated with significantly lower rates of bleed- ing and death from cardiovascular causes.S4.1.1-11 Treatment of patients with AF with edoxaban, either 30 mg or 60 mg, should be based on assessment of the risks of stroke and bleeding. In ENGAGE-TIMI 48 (Effective Anticoagulation With Recommendations for Selecting an Anticoagulant Regimen Balancing Risks and Benefits (Continued) COR LOE Recommendations Recommendations for Selecting an Anticoagulant Regimen Balancing Risks and Benefits (Continued) COR LOE Recommendations CLINICAL STATEMENTS AND GUIDELINES Factor Xa Next Generation in Atrial Fibrillation Thrombolysis in Myocardial Infarction 48), the rate of systemic embolism and stroke was 1.5% with warfarin, compared with 1.2% with 60 mg of edoxaban (hazard ratio [HR]: 0.79; 97.5% CI: with 30 mg of edoxaban (HR: 1.07; 97.5% CI: 0.87 1.31; p=0.005 for noninferiority). The rate of major bleeding was 3.4% with warfarin, ver- sus 2.8% with 60 mg of edoxaban (HR: 0.80; mg of edoxaban (HR: 0.47; 95% CI: 0.41 0.55; In the 2014 AF Guideline, the presence of a prior stroke, a prior transient isch- emic attack, or a CHA2 -VASc score of 2 or greater was an indication to consider oral antico- agulants. In the present focused update, we are adding precision to the CHA2 -VASc scoring system on the basis of new published informa- tion. The COR and LOE of warfarin, dabigatran, rivaroxaban, and apixaban are unchanged from the 2014 AF Guideline. comparing NOACs with warfarin.


The COR and LOE of warfarin, dabigatran, rivaroxaban, and apixaban are unchanged from the 2014 AF Guideline. comparing NOACs with warfarin. There was consistent evi- dence of at least noninferiority for the combined endpoint of stroke or systemic embolism. When combined with a superior safety profile, they are recommended as firstline therapy for eligible patients. 4. The recommendation is similar to the 2014 AF Guideline. New evidence has appeared that emphasizes the substantial variation across dif- ferent cohorts of patients with AF, including various non-European populations, in overall stroke rates for a given CHA2 -VASc point Additional approaches to stroke risk prediction and serious net clinical outcome pre- diction in selected patients with AF, including for specific anticoagulant management, have been Anticoagulation for AF and hypertrophic cardiomyopathy remain the same as in the 2014 AF Guideline. Patients with bioprosthetic heart valves were not included in studies validating the CHA2 - VASc scoring system. For bioprosthetic valves, very limited published experience exists for the use of the CHA2 -VASc scoring system for long-term assessment of thromboembolism risk in patients with AF. In 1 brief report in patients with AF, increasing age and the CHA2 -VASc score were independent predictors of thrombo- embolic events. In these patients with AF, a low -VASc score was associated with low thromboembolic risk regardless of whether the patients had bioprosthetic valves.S4.1.1-43 In addi- tion, in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; apixaban) and ENGAGE AF- TIMI 48 (edoxaban) AF trials, small numbers of these patients (with mitral or aortic bioprosthet- ic valve implants) were included.


In these patients with AF, a low -VASc score was associated with low thromboembolic risk regardless of whether the patients had bioprosthetic valves.S4.1.1-43 In addi- tion, in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; apixaban) and ENGAGE AF- TIMI 48 (edoxaban) AF trials, small numbers of these patients (with mitral or aortic bioprosthet- ic valve implants) were included. In these small subgroups, the findings suggested that apixaban (41 patients) and edoxaban (191 patients) ap- peared to be equitable alternatives to warfarin in patients with AF and remote bioprosthetic Although short- term anticoagulation of bioprosthetic valves after implantation is standard practice, further study is needed before the routine long-term use of the CHA2 -VASc score can be recom- mended in AF patients with bioprosthetic heart 5. One mechanical aortic valve replacement has FDA- approved recommendations of an INR of 1.5 to 2.0 (3 months after implantation) along with low- dose aspirin, based on a limited clinical trial.S4.1.1-46 This trial was designed to test whether it is safe and effective to treat patients with less aggres- sive anticoagulant therapy after implantation of an approved mechanical valve prosthesis (On-X). Although patients with AF were not excluded, very few were enrolled (see also the AHA/ACC valvular heart disease guidelinesS4.1.1-18 S4.1.1-19 ). 7. All 4 NOACs with FDA approval for use in patients with AF have dosing defined by renal function (creatinine or CrCl using the Cockcroft-Gault equation).


All 4 NOACs with FDA approval for use in patients with AF have dosing defined by renal function (creatinine or CrCl using the Cockcroft-Gault equation). Apixaban adds additional dosing considerations of age 80 years or weight 60 Edoxaban is not approved for use in patients with poor renal function (CrCl <30 mL/ min) or upper-range renal function (CrCl >95 mL/ Renal function should be regularly monitored and CrCl calculated at an interval that depends on the individual degree of renal dys- function and likelihood of fluctuation, and dose adjustments should be made according to FDA In addition, for the factor Xa inhibitors, hepatic function should occasionally be monitored. NOACs are not recommended for use in patients with severe hepatic dysfunction. 11. Edoxaban (30 mg or 60 mg once daily) was stud- ied in a large randomized prospective AF trial (ENGAGE AF-TIMI 48); it was noninferior to war- farin with regard to the prevention of stroke or systemic embolization and was associated with significantly lower rates of bleeding and death from cardiovascular causes.S4.1.1-11 12. Many risk factors contribute to the increased risk of stroke in patients with AF as expressed in the -VASc score. The evidence for female sex as a risk factor has been assessed in many stud- ies. Most studies support the finding that females CLINICAL STATEMENTS AND GUIDELINES with AF are at increased risk of stroke. One meta- elevated risk of stroke in females with AF, with the risk appearing greatest for females 75 years Recent studies have suggested that female sex, in the absence of other AF risk fac- -VASc score of 0 in males and 1 in females), carries a low stroke risk that is similar to males.


One meta- elevated risk of stroke in females with AF, with the risk appearing greatest for females 75 years Recent studies have suggested that female sex, in the absence of other AF risk fac- -VASc score of 0 in males and 1 in females), carries a low stroke risk that is similar to males. The excess risk for females was espe- cially evident among those with 2 non sex- related stroke risk factors; thus, female sex is a risk modifier and is age dependent.S4.1.1-49 Adding female sex to the CHA2 -VASc score matters for age >65 years or 2 non sex-related stroke 13. Patients with end-stage CKD who receive dialy- sis have increased prevalence of AF and other associated risk factors for strokeS4.1.1-50 and have increased bleeding risk.S4.1.1-50 S4.1.1-52 Warfarin, when studied in large retrospective studies, has been shown to offer protection from cardiovas- cular events without increasing bleeding;S4.1.1-29 however, in a recent meta-analysis, warfarin did not offer reduction in deaths, ischemic events, or strokes but increased the incidence of major Limited data exist on single- and multiple- dose apixaban (2.5 mg or 5 mg) in patients with AF and CKD on dialysis compared to healthy Patients with CKD on di- alysis accumulate apixaban (increase in apixaban area-under-the-plasma-concentration-versus- time-curve and trough drug levels), and apixaban 2.5 mg twice daily resulted in steady-state drug exposure comparable to 5 mg twice daily in pa- tients with preserved renal function. Dialysis had a limited impact on apixaban clearance. Bleed- ing complications were decreased. A recent trial compared apixaban (5 mg versus 2.5 mg twice daily) and warfarin in dialysis-dependent patients with AF. Patients receiving standard-dose apixa- ban (5 mg) had a lower risk of stroke/embolism than those receiving low-dose apixaban (2.5 mg) and warfarin.


Patients receiving standard-dose apixa- ban (5 mg) had a lower risk of stroke/embolism than those receiving low-dose apixaban (2.5 mg) and warfarin. Standard-dose apixaban was associated with a lower risk of death than that observed with low-dose apixaban and warfarin, and there was a lower risk of major bleeding with apixaban than with warfarin.S4.1.1-30 Use of warfa- rin or apixaban might be reasonable in dialysis- dependent patients with AF, but further study is warranted. 14. Edoxaban (30 mg or 60 mg once daily) was studied in ENGAGE AF-TIMI 48; it was found to be noninferior to warfarin with regard to the prevention of stroke or systemic emboliza- tion and was associated with significantly lower rates of bleeding and death from cardiovascular 15. There has been uncertainty about whether anti- coagulation is warranted in men and women who have AF with a CHA2 -VASc score of 1 or 2, respectively. Women with AF are likely to be older and have an increased risk of Female sex alone, however, does not convey increased risk in the absence of Recent studies of a large community-based cohort of patients with AF addressed the benefit of anticoagulation among patients with AF who have 1 non sex- related AF risk factor (CHA2 -VASc score of The authors found that nonanticoagulated patients with AF who had 1 non sex-related stroke risk fac- -VASc score of 1 versus 0 in males and 2 vs. 1 in females) had an increased risk of serious cardiovascular events during follow-up. Importantly, warfarin anticoagulation use was associated with a small positive net clinical ben- efit (measured as ischemic stroke reduction bal- anced against increased intracranial hemorrhage) compared with no anticoagulation or antiplatelet therapy use. Similar studies with NOACs in such patients are needed. 16.


Similar studies with NOACs in such patients are needed. 16. Edoxaban is 50% renally excreted and dosed once a day; it is not recommended in patients with end- stage renal disease or on dialysis.S4.1.1-11 Limited single-dose pharmacokinetic data have been published for rivaroxaban use in patients with end-stage kidney disease on dialysis.S4.1.1-59,S4.1.1-60 Dabigatran and rivaroxaban have been stud- ied by using prescription patterns in a dialysis Dabigatran and rivaroxaban were associated with a higher risk of hospi- talization or death from bleeding than that of 17. The RE-ALIGN trial (Randomized, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients After Heart Valve Replacement) was a multicenter, prospec- tive, randomized, phase II dose-validation study of dabigatran versus warfarin that enrolled patients (18-75 years of age) with one of the following: mechanical valve replacement in the aortic or mitral position (or both) within the prior 7 days (population A) or mechanical mitral valve (with or without aortic valve) replacement more than 3 months before randomization (population B). The trial was stopped after it had enrolled 252 patients because of unacceptable thromboembolic and bleeding event rates in the dabigatran group. Similar drug safety and efficacy information is lacking for mechanical CLINICAL STATEMENTS AND GUIDELINES heart valves and rivaroxaban, apixaban, and edoxaban. On the basis of the outcomes of the RE-ALIGN trial, the presence of a mechanical heart valve is considered a contraindication to all 4.2. Anticoagulant Options (Modified From Section 4.2., Antithrombotic Options, in the 2014 AF Guideline) 4.2.2.2. Non Vitamin K Oral Anticoagulants (Modified From Section 4.2.2.2., New Target-Specific Oral Anticoagulants, in the 2014 AF Guideline) Most NOACs represent an advance in therapeutic safety when compared with warfarin for prevention of throm- boembolism in patients with AF.


Non Vitamin K Oral Anticoagulants (Modified From Section 4.2.2.2., New Target-Specific Oral Anticoagulants, in the 2014 AF Guideline) Most NOACs represent an advance in therapeutic safety when compared with warfarin for prevention of throm- boembolism in patients with AF. The NOAC AF trials demonstrated that NOACs are noninferiorS4.2.2.2-1,S4.2.2.2-2 to warfarin in preventing stroke or thromboembolism. NOACs reduce intracra- nial bleeding as compared with warfarin.S4.2.2.2-1 S4.2.2.2-5 Although no direct RCT data are available, limited data comparing individual NOACs to one another are emerging from meta-analyses of the original NOAC clinical trialsS4.2.2.2-6 and registries and patient and more data are expected. Specific NOACs, such as apixaban, may have lower risks of bleeding (including intracranial hemorrhage) and improved efficacy for stroke prevention, whereas the risk of bleeding for rivaroxaban is comparable to that of warfarin. In other studies, uninterrupted dabi- gatran had a more favorable outcome than warfarin in ablation of AF (RE-CIRCUIT Trial [Uninterrupted Dabigatran Etexilate in Comparison to Uninterrupted Warfarin in Pulmonary Vein Ablation]).S4.2.2.2-15 Over time, NOACs (particularly dabigatran and rivaroxaban) may be associated with lower risks of adverse renal outcomes than warfarin in patients with AF.S4.2.2.2-16 Among older adults with AF receiving anticoagula- tion, dabigatran was associated with a lower risk of osteoporotic fracture than warfarin.S4.2.2.2-17 Data on drug interactions with NOACs are emerging.S4.2.2.2-18 Interpretation of these data requires careful consider- ation of trial design, including factors such as absence of control groups, incomplete laboratory and histori- cal data, missing data for some drugs (particularly edoxaban), and varying NOAC drug doses (some ap- proved doses in the United States differ from those in Europe). Head-to-head prospective RCT data for NO- ACs are needed for further evaluation of comparative bleeding risk and effectiveness.


Head-to-head prospective RCT data for NO- ACs are needed for further evaluation of comparative bleeding risk and effectiveness. Commercial assays to measure NOAC serum levels are now available, but reference ranges derived from published literature are variable and are not well cor- related with safety, efficacy, and clinical outcomes. Indi- cations for measurement of NOAC serum levels might include: Measurement of drug levels in patients undergo- ing urgent surgical procedures. Uncovering accumulation of potentially toxic drug levels in patients with CKD or those undergoing dialysis. Detection of potential drug drug interactions to guide dose adjustment. Evaluation of drug absorption in severely obese patients (body mass index >35 or weight >120 kg) Assessment of patient adherence. 4.3. Interruption and Bridging Anticoagulation Recommendations for Interruption and Bridging Anticoagulation Referenced studies that support new or modified recommendations are summarized in Online Data Supplement 3. COR LOE Recommendations I C Bridging therapy with unfractionated heparin or low-molecular-weight heparin is recommended for patients with AF and a mechanical heart valve undergoing procedures that require interruption of warfarin. Decisions on bridging therapy should balance the risks of stroke and bleeding. I B-R For patients with AF without mechanical heart valves who require interruption of warfarin for procedures, decisions about bridging therapy (unfractionated heparin or low-molecular-weight heparin) should balance the risks of stroke and bleeding and the duration of time a patient will not be MODIFIED: LOE was updated from C to B-R because of new evidence. (Section 4.1. in the 2014 AF Guideline) I B-NR Idarucizumab is recommended for the reversal of dabigatran in the event of life-threatening bleeding or an urgent NEW: New evidence has been published about idarucizumab to support LOE B-NR.


(Section 4.1. in the 2014 AF Guideline) I B-NR Idarucizumab is recommended for the reversal of dabigatran in the event of life-threatening bleeding or an urgent NEW: New evidence has been published about idarucizumab to support LOE B-NR. IIa B-NR Andexanet alfa can be useful for the reversal of rivaroxaban and apixaban in the event of life- threatening or uncontrolled bleeding.S4.3-3,S4.3-4 NEW: New evidence has been published about andexanet alfa to support LOE B-NR. Recommendation-Specific Supportive Text (New or Modified) 2. The BRIDGE (Bridging Anticoagulation in Patients who Require Temporary Interruption CLINICAL STATEMENTS AND GUIDELINES of Warfarin Therapy for an Elective Invasive Procedure or Surgery) study was a randomized, double-blind, placebo-controlled trial of bridg- ing versus no bridging in 1 884 patients with AF (except with moderate to severe mitral stenosis or a mechanical heart valve) requiring peripro- cedural interruption of warfarin therapy.S4.3-1 Absence of bridging was found to be noninfe- rior to bridging with low-molecular-weight hep- arin for prevention of arterial thromboembolism and was found to decrease the risk of bleeding. Bridging anticoagulation may be appropriate only in patients (on warfarin) with a very high thromboembolic risk. 3. The analysis of 503 patients from the RE-VERSE AD (Reversal Effects of Idarucizumab on Active Dabigatran) trial found that idarucizumab, a monoclonal antibody fragment that binds dabig- atran, rapidly normalized hemostasis and reduced levels of circulating dabigatran in subjects on dab- igatran who had serious bleeding or required an Idarucizumab has received full FDA approval. 4. Andexanet alfa (coagulation factor Xa [recom- binant], inactivated-zhzo) is a bioengineered, recombinant modified protein designed to serve as an antidote against direct factor Xa inhibitors. It was reported to reverse the effects of rivaroxaban and was approved under the FDA s accelerated-approval pathway on the basis of effects in healthy volunteers.


It was reported to reverse the effects of rivaroxaban and was approved under the FDA s accelerated-approval pathway on the basis of effects in healthy volunteers. Continued approval may be contingent on postmarketing studies to demonstrate an improvement in hemo- stasis in patients. 4.4. Nonpharmacological Stroke Prevention 4.4.1. Percutaneous Approaches to Occlude the LAA Recommendation for Percutaneous Approaches to Occlude the LAA Referenced studies that support the new recommendation are summarized in Online Data Supplement 4. COR LOE Recommendation IIb B-NR Percutaneous LAA occlusion may be considered in patients with AF at increased risk of stroke who have contraindications to long-term NEW: Clinical trial data and FDA approval of the Watchman device necessitated this recommendation. Recommendation-Specific Supportive Text (New) 1. Percutaneous LAA occlusion with the Watchman device has been compared with warfarin in patients with AF (in the absence of moderate to severe mitral stenosis or a mechanical heart valve) at increased risk of stroke in 2 RCTs: the PROTECT AF (WATCHMAN Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation)S4.4.1-1 and the PREVAIL (Evaluation of the WATCHMAN LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy)S4.4.1-2 trials. A meta-analysis combining data from these 2 trials and their regis- tries demonstrated that patients receiving the device had significantly fewer hemorrhagic strokes than did those receiving warfarin, but there was an increase in ischemic strokes in the device group.S4.4.1-3 However, when periprocedural events were excluded, the dif- ference in ischemic strokes was not significant. Oral anticoagulation remains the preferred ther- apy for stroke prevention for most patients with AF and elevated stroke risk. However, for patients who are poor candidates for long-term oral anticoagu- lation (because of the propensity for bleeding or poor drug tolerance or adherence), the Watchman device provides an alternative.


However, for patients who are poor candidates for long-term oral anticoagu- lation (because of the propensity for bleeding or poor drug tolerance or adherence), the Watchman device provides an alternative. There are important differences in wording between the FDA approval and the Centers for Medicare & Medicaid Services (CMS) approval. In the FDA approval, the device was restricted to patients who were deemed suitable for long-term warfarin (mirroring the inclusion criteria for enrollment in the clinical trials) but had an ap- propriate rationale to seek a nonpharmacological alternative to warfarin. Conversely, CMS states that the device is an option for patients who are suitable for short-term warfarin but deemed unable to take long-term oral anticoagulation. CMS has specified that patients should have a CHADS2 score 2 or a -VASc score 3 to be considered for the device. A number of unresolved issues remain, in- cluding the optimal patient selection and peripro- cedural antithrombotic regimen. The current FDA labeling specifies that patients should be deemed suitable for anticoagulation and, in particular, a period of periprocedural anticoagulation. Patients unable to take oral anticoagulation were excluded from the Watchman RCTs. However, there is in- creasing experience outside the United States with LAA closure in oral anticoagulation ineligible pa- tients using an antiplatelet regimen only,S4.4.1-6,S4.4.1-7 and this is the focus of an ongoing RCT.S4.4.1-8 CLINICAL STATEMENTS AND GUIDELINES 4.4.2. Cardiac Surgery LAA Occlusion/Excision Recommendation for Cardiac Surgery LAA Occlusion/Excision Referenced studies that support the modified recommendation are summarized in Online Data Supplement 5. COR LOE Recommendation IIb B-NR Surgical occlusion of the LAA may be considered in patients with AF undergoing , as a component of an overall heart team approach to the management of AF. MODIFIED: LOE was updated from C to B-NR because of new evidence. Recommendation-Specific Supportive Text (Modified) 1.


MODIFIED: LOE was updated from C to B-NR because of new evidence. Recommendation-Specific Supportive Text (Modified) 1. New evidence exists supporting surgical LAA occlusion in patients with a history of AF. An observational study evaluated the association between surgical LAA occlusion (usually with sur- gical atrial ablation) performed concurrently with cardiac operations in older patients with a history of AF and the risk of postoperative thromboem- The authors used patient information from the Society of Thoracic Surgeons Adult Cardiac Surgery Database registry, which contains perioperative information with short- term (mainly 30-day) outcomes. The study linked the Society of Thoracic Surgeons Adult Cardiac Surgery Database patient information to Medicare claims data (age 65 years), with the primary out- come of readmission within 3 years of operation for thromboembolism (stroke, transient ischemic attack, or systemic embolism). The study identi- fied 10524 patients who underwent cardiac sur- gical procedures, including 3892 patients (37%) with surgical LAA occlusion. At a mean follow-up of 2.6 years, surgical LAA occlusion, compared with no LAA occlusion, was associated with lower unadjusted rates of readmission for thromboem- bolism (4.2% versus 6.2%), all-cause mortality (17.3% versus 23.9%), and the composite end- point (20.5% versus 28.7%) but no significant difference in rates of hemorrhagic stroke (0.9% each). These findings suggest that surgical LAA occlusion may be associated with reduced post- operative thromboembolic events in older patients with a history of AF. In subgroup analyses stratified by anticoagulation status at hospital discharge, patients with a history of AF who received LAA occlusion without postoperative anticoagulation had a significantly lower thrombo- embolism rate than those who received neither LAA occlusion nor anticoagulation.


In subgroup analyses stratified by anticoagulation status at hospital discharge, patients with a history of AF who received LAA occlusion without postoperative anticoagulation had a significantly lower thrombo- embolism rate than those who received neither LAA occlusion nor anticoagulation. There also was no signif- icant difference in the risk of thromboembolism among patients with a history of AF discharged with antico- agulation therapy, whether they received surgical LAA occlusion or not. These data support a role for antico- agulation in patients with a history of AF, particularly in patients not receiving LAA occlusion. A propensity-matched analysis of prophylactic surgi- cal LAA occlusion in patients undergoing cardiac sur- gery did not demonstrate an association between LAA occlusion and long-term thromboembolic events.S4.4.2-2 The propensity-matched LAA occlusion and non LAA occlusion groups were relatively small (461 patients per group), and fewer than half the patients in each group had a history of AF. The study did show that surgical LAA occlusion, which often was incomplete, was asso- ciated with increased risk of early postoperative AF, but it did not influence the risk of stroke or death. There are several important limitations to these stud- ies, and future RCTs may be valuable. 6. RHYTHM CONTROL 6.1. Electrical and Pharmacological Cardioversion of AF and Atrial Flutter 6.1.1. Prevention of Thromboembolism Recommendations for Prevention of Thromboembolism Referenced studies that support modified recommendations are summarized in Online Data Supplement 6.


Prevention of Thromboembolism Recommendations for Prevention of Thromboembolism Referenced studies that support modified recommendations are summarized in Online Data Supplement 6. COR LOE Recommendations I B-R For patients with AF or atrial flutter of 48 hours duration or longer, or when the duration of AF is unknown, anticoagulation with warfarin (INR 2.0 to 3.0), a factor Xa inhibitor, or direct thrombin inhibitor is recommended for at least 3 weeks before and at least 4 weeks after cardioversion, regardless of the CHA2 -VASc score or the method (electrical or pharmacological) used to restore sinus rhythm.S6.1.1-1 S6.1.1-12 MODIFIED: The 2014 AF Guideline recommendation for use of warfarin around the time of cardioversion was combined with the 2014 AF Guideline recommendation for NOACs to create a single recommendation. This combined recommendation was updated to COR I/LOE B-R from COR IIa/LOE C for NOACs in the 2014 AF Guideline on the basis of additional trials that have evaluated the use of NOACs with cardioversion. I C For patients with AF or atrial flutter of more than 48 hours duration or unknown duration that requires immediate cardioversion for hemodynamic instability, anticoagulation should be initiated as soon as possible and continued for at least 4 weeks after cardioversion unless contraindicated. CLINICAL STATEMENTS AND GUIDELINES I C-EO After cardioversion for AF of any duration, the decision about long-term anticoagulation therapy should be based on the thromboembolic risk profile and bleeding risk profile. MODIFIED: The 2014 AF Guideline recommendation was strengthened with the addition of bleeding risk profile to the long- term anticoagulation decision-making process.


MODIFIED: The 2014 AF Guideline recommendation was strengthened with the addition of bleeding risk profile to the long- term anticoagulation decision-making process. IIa B-NR For patients with AF or atrial flutter of less than 48 hours duration with a CHA2 - VASc score of 2 or greater in men and 3 or greater in women, administration of heparin, a factor Xa inhibitor, or a direct thrombin inhibitor is reasonable as soon as possible before cardioversion, followed by long-term MODIFIED: Recommendation COR was changed from I in the 2014 AF Guideline to IIa, and LOE was changed from C in the 2014 AF Guideline to B-NR. In addition, a specific -VASc score is now specified. IIa B For patients with AF or atrial flutter of 48 hours duration or longer or of unknown duration who have not been anticoagulated for the preceding 3 weeks, it is reasonable to perform transesophageal echocardiography before cardioversion and proceed with cardioversion if no left atrial thrombus is identified, including in the LAA, provided that anticoagulation is achieved before transesophageal echocardiography and maintained after cardioversion for at least 4 IIb B-NR For patients with AF or atrial flutter of less than 48 hours duration with a CHA2 - VASc score of 0 in men or 1 in women, administration of heparin, a factor Xa inhibitor, or a direct thrombin inhibitor, versus no anticoagulant therapy, may be considered before cardioversion, without the need for postcardioversion oral MODIFIED: Recommendation LOE was changed from C in the 2014 AF Guideline to B-NR to reflect evidence from 2 registry studies and to include specific CHA2 -VASc scores derived from study results. Recommendation-Specific Supportive Text (New or Modified) 1.


IIa B For patients with AF or atrial flutter of 48 hours duration or longer or of unknown duration who have not been anticoagulated for the preceding 3 weeks, it is reasonable to perform transesophageal echocardiography before cardioversion and proceed with cardioversion if no left atrial thrombus is identified, including in the LAA, provided that anticoagulation is achieved before transesophageal echocardiography and maintained after cardioversion for at least 4 IIb B-NR For patients with AF or atrial flutter of less than 48 hours duration with a CHA2 - VASc score of 0 in men or 1 in women, administration of heparin, a factor Xa inhibitor, or a direct thrombin inhibitor, versus no anticoagulant therapy, may be considered before cardioversion, without the need for postcardioversion oral MODIFIED: Recommendation LOE was changed from C in the 2014 AF Guideline to B-NR to reflect evidence from 2 registry studies and to include specific CHA2 -VASc scores derived from study results. Recommendation-Specific Supportive Text (New or Modified) 1. Three prospective RCTs have evaluated the safety and efficacy of newly initiated factor Xa inhibi- tors (rivaroxaban and apixaban) for cardioversion as an alternative to warfarin.S6.1.1-7,S6.1.1-8,S6.1.1-17 In addition, retrospective analyses have been per- formed on the subset of patients undergoing cardioversion within the context of the larger randomized trials that compared each of the FDA-approved NOACs with warfarin for throm- boembolism prevention with AF. The results were consistent and support the assertion that NOACs are an effective and safe alternative to warfarin for patients undergoing cardioversion. An alter- native to waiting 3 weeks before cardioversion is to perform transesophageal echocardiography to exclude thrombus (see separate recommen- dation in this section). The decision about long- term anticoagulant therapy (beyond 4 weeks) is based on the thromboembolic risk profile (Section 4) and bleeding risk profile.


The decision about long- term anticoagulant therapy (beyond 4 weeks) is based on the thromboembolic risk profile (Section 4) and bleeding risk profile. The 48-hour rule has also been questioned, because delay to car- dioversion of 12 hours or longer from symp- tom onset was associated with a greater risk of thromboembolic complications compared to cardioversion of less than 12 hours (1.1% versus and the risk of thromboembolic com- plications with cardioversion of 12 hour or longer increases substantially in patients >75 years of age and in women.S6.1.1-19 4. The data supporting the safety of current prac- tices of cardioversion of AF without oral anticoag- ulation in patients with AF duration <48 hours are limited. Two recent retrospective studies demon- strate that the risk of thromboembolic complica- tion after a cardioversion for AF lasting <48 hours is in the range of 0.7% to 1.1%, with higher risk in patients with risk factors that include female sex, HF, and diabetes mellitus, whereas patients <60 years of age without thromboembolic risk factors and those with postoperative AF appear to have a lower risk.S6.1.1-13,S6.1.1-14 cardioversions in 484 patients), the risk of throm- boembolism was nearly 5 times higher in patients without therapeutic anticoagulation than in those on therapeutic anticoagulation with either warfa- rin or heparin. All events in that study occurred in patients with a CHA2 -VASc score of 2.S6.1.1-14 In the absence of randomized trials, the risk of thromboembolic events should be weighed against the risk of anticoagulant-related bleeding for the individual patient. 6. Two recent retrospective studies evaluated the risk of thromboembolism in patients after cardio- version for AF lasting <48 hours.


Two recent retrospective studies evaluated the risk of thromboembolism in patients after cardio- version for AF lasting <48 hours. In 1 study (567 cardioversions in 484 patients), the risk of throm- boembolism was nearly 5 times higher in patients without therapeutic anticoagulation than in those on therapeutic anticoagulation with either warfa- rin or heparin, with no events in patients with a -VASc score of <2.S6.1.1-14 In the second study, for patients with AF lasting <48 hours and -VASc score 1, the overall event rate was low (0.4%), but this group accounted for 10 of the 38 thromboembolic events (26%) that occurred in the study.S6.1.1-13 These studies agree with prior studies of cardioversion in short-term In the absence of randomized trials, the risk of thromboembolic events should be weighed Recommendations for Prevention of Thromboembolism (Continued) COR LOE Recommendations CLINICAL STATEMENTS AND GUIDELINES against the risk of anticoagulant-related bleeding for the individual patient. 6.3. AF Catheter Ablation to Maintain Sinus Rhythm 6.3.4. Catheter Ablation in HF Recommendation for Catheter Ablation in HF Referenced studies that support the new recommendation are summarized in Online Data Supplement 7. COR LOE Recommendation IIb B-R AF catheter ablation may be reasonable in selected patients with symptomatic AF and HF with reduced left ventricular (LV) ejection fraction (HFrEF) to potentially lower mortality rate and reduce hospitalization for HF.S6.3.4-1,S6.3.4-2 NEW: New evidence, including data on improved mortality rate, has been published for AF catheter ablation compared with medical therapy in patients with HF. Recommendation-Specific Supportive Text (New) 1.


COR LOE Recommendation IIb B-R AF catheter ablation may be reasonable in selected patients with symptomatic AF and HF with reduced left ventricular (LV) ejection fraction (HFrEF) to potentially lower mortality rate and reduce hospitalization for HF.S6.3.4-1,S6.3.4-2 NEW: New evidence, including data on improved mortality rate, has been published for AF catheter ablation compared with medical therapy in patients with HF. Recommendation-Specific Supportive Text (New) 1. In an RCT (CASTLE-AF [Catheter Ablation vs. Standard Conventional Treatment in Patients With LV Dysfunction and AF]), selected patients with HFrEF with paroxysmal or persistent AF and an implanted cardioverter-defibrillator or cardiac resynchronization therapy defibrillator device who did not respond to or could not take antiarrhyth- mic drugs were randomized to receive AF catheter ablation versus medical therapy (rate or rhythm control) in addition to guideline-directed manage- ment and therapy for HFrEF.S6.3.4-1 Patients in the AF catheter ablation group had significantly reduced overall mortality rate, reduced rate of hospitaliza- tion for worsening HF, and improved LV ejection fraction as compared with the medical therapy group, and according to device interrogation, more patients in the AF catheter ablation group were in sinus rhythm. An additional RCT in a population of patients with persistent AF, HFrEF, and an implanted cardioverter-defibrillator or cardiac resynchroniza- tion therapy defibrillator device demonstrated that AF catheter ablation was superior to amiodarone for maintenance of sinus rhythm, with second- ary endpoint analyses suggesting a lower rate of unplanned hospitalization and death.S6.3.4-2 Both studies have limitations, including relatively small and highly selected patient populations. Further, larger studies are needed to validate these findings.


An additional RCT in a population of patients with persistent AF, HFrEF, and an implanted cardioverter-defibrillator or cardiac resynchroniza- tion therapy defibrillator device demonstrated that AF catheter ablation was superior to amiodarone for maintenance of sinus rhythm, with second- ary endpoint analyses suggesting a lower rate of unplanned hospitalization and death.S6.3.4-2 Both studies have limitations, including relatively small and highly selected patient populations. Further, larger studies are needed to validate these findings. Other small studies conducted in patients with AF and HFrEF have shown the superiority of AF ablation over antiarrhythmic drugs in the mainte- nance of sinus rhythm and in outcomes such as improved LV ejection fraction, performance in a 6-minute walk test, and quality of life.S6.3.4-3,S6.3.4-4 However, the recent CABANA (Catheter Ablation verses Anti-arrhythmic Drug Therapy for Atrial Fi- brillation) trial (n=2204 patients randomized to either catheter ablation or drug therapy) showed that AF ablation was not superior to drug therapy for the primary cardiovascular outcomes of death, disabling stroke, serious bleeding, or cardiac arrest at 5 years among patients with new-onset or un- treated AF that required therapy.S6.3.4-5,S6.3.4-6 7. SPECIFIC PATIENT GROUPS AND AF 7.4. AF Complicating ACS Recommendations for AF Complicating ACS Referenced studies that support new or modified recommendations are summarized in Online Data Supplement 8. COR LOE Recommendations I B-R For patients with ACS and AF at increased risk of systemic thromboembolism (based -VASc risk score of 2 or greater), anticoagulation is recommended unless the bleeding risk exceeds the expected MODIFIED: New published data are available. LOE was updated from C in the 2014 AF Guideline to B-R. Anticoagulation options are described in supportive text. I C Urgent direct-current cardioversion of new-onset AF in the setting of ACS is recommended for patients with hemodynamic compromise, ongoing ischemia, or inadequate rate control.


I C Urgent direct-current cardioversion of new-onset AF in the setting of ACS is recommended for patients with hemodynamic compromise, ongoing ischemia, or inadequate rate control. I C Intravenous beta blockers are recommended to slow a rapid ventricular response to AF in patients with ACS who do not display HF, hemodynamic instability, or bronchospasm. IIa B-NR If triple therapy (oral anticoagulant, aspirin, inhibitor) is prescribed for patients with AF at increased risk of stroke (based -VASc risk score of 2 or greater) who have undergone percutaneous coronary intervention (PCI) with stenting for ACS, it is reasonable to choose clopidogrel in preference to prasugrel.S7.4-4,S7.4-5 NEW: New published data are available. IIa B-R In patients with AF at increased risk of stroke (based on CHA2 -VASc risk score of 2 or greater) who have undergone PCI with stenting for ACS, double therapy with inhibitor (clopidogrel or ticagrelor) and dose-adjusted vitamin K antagonist is reasonable to reduce the risk of bleeding as compared with triple therapy.S7.4-3,S7.4-6 S7.4-8 NEW: New RCT data and data from 2 registries and a retrospective cohort study are available. IIa B-R In patients with AF at increased risk of stroke (based on CHA2 -VASc risk score of 2 or greater) who have undergone PCI with stenting for ACS, double therapy with inhibitors (clopidogrel) and low-dose rivaroxaban 15 mg daily is reasonable to reduce the risk of bleeding as compared with triple therapy.S7.4-2 NEW: New published data are available.


IIa B-R In patients with AF at increased risk of stroke (based on CHA2 -VASc risk score of 2 or greater) who have undergone PCI with stenting for ACS, double therapy with inhibitors (clopidogrel) and low-dose rivaroxaban 15 mg daily is reasonable to reduce the risk of bleeding as compared with triple therapy.S7.4-2 NEW: New published data are available. CLINICAL STATEMENTS AND GUIDELINES IIa B-R In patients with AF at increased risk of stroke (based on CHA2 -VASc risk score of 2 or greater) who have undergone PCI with stenting for ACS, double therapy with a inhibitor (clopidogrel) and dabigatran 150 mg twice daily is reasonable to reduce the risk of bleeding as compared with triple NEW: New published data are available. IIb B-R If triple therapy (oral anticoagulant, aspirin, inhibitor) is prescribed for patients with AF who are at increased risk of stroke (based on CHA2 -VASc risk score of 2 or greater) and who have undergone PCI with stenting (drug eluting or bare metal) for ACS, a transition to double therapy (oral anticoagulant and P2Y12 inhibitor) at 4 to 6 weeks may be considered.S7.4-9,S7.4-10 NEW: New published data are available. IIb C Administration of amiodarone or digoxin may be considered to slow a rapid ventricular response in patients with ACS and AF associated with severe LV dysfunction and HF or hemodynamic instability. IIb C Administration of nondihydropyridine calcium antagonists may be considered to slow a rapid ventricular response in patients with ACS and AF only in the absence of significant HF or hemodynamic instability.


IIb C Administration of nondihydropyridine calcium antagonists may be considered to slow a rapid ventricular response in patients with ACS and AF only in the absence of significant HF or hemodynamic instability. Synopsis The incidence of AF in patients with ACS ranges from 10% to 21% and increases with patient age and se- verity of myocardial infarction (MI).S7.4-11,S7.4-12 In the Medicare population, AF is associated with increased in-hospital mortality rate (25.3% with AF versus versus 19.1%), and 1-year mortality rate (48.3% ver- With multivariate adjustment, AF re- mains an independent predictor of death: in hospital (odds ratio: 1.21), at 30 days (odds ratio: 1.20), and at 1 year (odds ratio: 1.34).S7.4-12 Patients who devel- op AF during hospitalization have a worse prognosis than those with AF on admission.S7.4-12 Stroke rates are higher in patients with MI and AF than in those without AF (3.1% for those with AF versus 1.3% for those in sinus rhythm).S7.4-11 Thus, AF is an indepen- dent predictor of poor long-term outcome in patients Patients treated for ACS normally require dual- antiplatelet therapy (DAPT) with aspirin plus a plate- receptor inhibitor and may require the ad- dition of warfarin or a NOAC ( triple therapy ) for primary prevention for patients with AF at increased risk of strokeS7.4-3 (Section 4.3.). An option is to con- sider double therapy the use of an oral antico- agulant plus a P2Y12 inhibitor without aspirin.S7.4-3 If triple therapy is used, efforts may be directed to minimize duration of triple therapy to a period of 4 to 6 weeks, as this is the period of greatest risk of stent thrombosis, especially in patients with ACS, such as ST-segment elevation MI.


An option is to con- sider double therapy the use of an oral antico- agulant plus a P2Y12 inhibitor without aspirin.S7.4-3 If triple therapy is used, efforts may be directed to minimize duration of triple therapy to a period of 4 to 6 weeks, as this is the period of greatest risk of stent thrombosis, especially in patients with ACS, such as ST-segment elevation MI. Use of DAPT alone may be considered for patients with ACS who have AF and a CHA2 -VASc score of 0 to 1, with recon- sideration of the indications for anticoagulation over Whereas Section 4.1.1. provides spe- cific guidance on the presence/absence of stroke risk associated with female sex in the CHA2 -VASc score, the randomized data set referenced in this section on double versus triple therapy in patients undergoing PCI (subset with ACS) does not present the data analysis stratified by sex; therefore, the rec- ommendation is provided in the context of overall -VASc score. The HAS-BLED score can be used to assess bleeding risk in patients for whom an- ticoagulation is being considered.S7.4-17 Urgent direct-current cardioversion is appropriate in patients with ACS presenting with new-onset AF and intractable ischemia, hemodynamic instability, or inade- quate rate control. Intravenous administration of a beta blocker is indicated for rate control in patients with ACS to reduce myocardial oxygen demands. Intrave- nous amiodarone is an appropriate alternative for rate control and may facilitate conversion to sinus rhythm. Digoxin may be considered in those with severe LV dys- function and HF or hemodynamic instability.


Digoxin may be considered in those with severe LV dys- function and HF or hemodynamic instability. However, recent data from the ARISTOTLE AF NOAC trial study population show that digoxin was independently as- sociated with higher mortality rate in patients with AF regardless of HF, and in patients with AF taking digoxin, the risk of death increased with higher serum digoxin Other meta-analysis studies sup- port these conclusions.S7.4-19 Treatment with angioten- sin-converting enzyme inhibitors appears to reduce the incidence of AF in patients with LV dysfunction after Recommendation-Specific Supportive Text (New or Modified) 1. This recommendation is modified to incor- porate the data from WOEST (What is the Optimal Antiplatelet & Anticoagulant Therapy in Patients With Oral Anticoagulation and and the recent evidence from PIONEER AF-PCI (Open-Label, Randomized, Controlled, Multicenter Study Exploring two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects With Atrial Fibrillation who Undergo Percutaneous Coronary and RE-DUAL PCI (Randomized Evaluation of Dual Antithrombotic Therapy With Dabigatran Versus Triple Therapy With Recommendations for AF Complicating ACS (Continued) COR LOE Recommendations CLINICAL STATEMENTS AND GUIDELINES Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary (see supportive text for recom- mendations 6 and 8 below). These 3 clinical tri- als enrolled both patients with stable ischemic disease and patients with ACS treated with PCI. These trials did not include patients with ACS managed medically. On the basis of these clinical trials, options for anticoagulants in this patient population include warfarin, rivaroxa- ban, and dabigatran. Although the use of the -VASc score has been validated only in several small studies of patients with AF and ACS, we believe it is reasonable to use this methodology to estimate the risk of systemic 4.


Although the use of the -VASc score has been validated only in several small studies of patients with AF and ACS, we believe it is reasonable to use this methodology to estimate the risk of systemic 4. A single-center prospective cohort study found that, as compared with triple therapy with clopi- dogrel, triple therapy with prasugrel was associ- ated with a higher incidence of Thrombolysis in Myocardial Infarction (TIMI) major or minor bleed- This finding was corroborated by the TRANSLATE-ACS (Treatment with Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome) study,S7.4-5 a mul- ticenter prospective cohort study of patients who underwent PCI for an acute MI. That study found that, as compared with triple therapy with clopi- dogrel, triple therapy with prasugrel was associ- ated with a higher incidence of BARC (Bleeding Academic Research Consortium) defined bleed- ing events. These events, however, were patient- reported bleeding events that did not require hospitalization. 5. WOEST was an RCT that showed that, as com- pared with triple therapy (aspirin, clopidogrel, and warfarin), double therapy with warfarin and clopidogrel was associated with fewer bleeding complications. WOEST, however, was not pow- ered to assess stent thrombosis.S7.4-3 Two other registry-based studies similarly showed that dou- ble therapy with warfarin and clopidogrel was not associated with higher risk of coronary isch- emia than triple therapy.S7.4-6,S7.4-7 Furthermore, a hospital-based retrospective cohort study found that double therapy with warfarin and ticagrelor had thrombotic and bleeding rates that were similar to those observed with triple The aforementioned studies were not based exclusively on patients with AF and ACS; patients with AF undergoing elective PCI for stable coronary artery disease were also included. 6.


WOEST, however, was not pow- ered to assess stent thrombosis.S7.4-3 Two other registry-based studies similarly showed that dou- ble therapy with warfarin and clopidogrel was not associated with higher risk of coronary isch- emia than triple therapy.S7.4-6,S7.4-7 Furthermore, a hospital-based retrospective cohort study found that double therapy with warfarin and ticagrelor had thrombotic and bleeding rates that were similar to those observed with triple The aforementioned studies were not based exclusively on patients with AF and ACS; patients with AF undergoing elective PCI for stable coronary artery disease were also included. 6. PIONEER AF-PCI was an international, multi- center, randomized, open-label trial of 2124 patients with AF (without moderate to severe mitral stenosis or a mechanical heart valve) who had undergone PCI with stenting. Patients were randomized in a 1:1:1 ratio to low-dose rivar- oxaban (15 mg once daily) plus a P2Y12 inhibitor for 12 months (Group 1); very-low-dose rivar- oxaban (2.5 mg twice daily) plus DAPT for 1, 6, or 12 months (Group 2); or standard therapy with a dose-adjusted vitamin K antagonist (once daily) plus DAPT for 1, 6, or 12 months (Group 3). Clopidogrel was the most common P2Y12 inhibitor used (>90%). The rates of clinically significant bleeding were lower in Groups 1 and 2 than in Group 3.S7.4-2 The rates of death from cardiovascular causes, MI, or stroke were similar It is important to note that the dose of rivaroxaban used in that study was lower than the dose recommended for stroke prophylaxis in AF. The study was not powered to evaluate risk of stent thrombosis or systemic 7. RE-DUAL PCI was an international, multicenter, randomized open-label trial of 2725 patients with nonvalvular AF who had undergone PCI with stenting.


RE-DUAL PCI was an international, multicenter, randomized open-label trial of 2725 patients with nonvalvular AF who had undergone PCI with stenting. Patients were randomized to receive 1 of 3 treatments: double therapy with dabigatran (110 mg twice daily) plus either clopidogrel or ticagrelor (110-mg dual-therapy group), double therapy with dabigatran (150 mg twice daily) plus either clopidogrel or ticagrelor (150-mg dual- therapy group), or triple therapy with warfarin plus aspirin ( 100 mg daily) and either clopido- grel or ticagrelor (triple-therapy group). The inci- dence of major or clinically relevant nonmajor bleeding was higher in the triple-therapy group than in the 110-mg dual-therapy group and the 150-mg dual-therapy group. In addition, the 2 dual-therapy groups combined were noninferior to the triple-therapy group with regard to the composite efficacy endpoint of thromboembolic events (MI, stroke, or systemic embolism), death, or unplanned revascularization. Clopidogrel was the most common P2Y12 inhibitor used (88%). Notably, the study was not powered to evaluate risk of stent thrombosis or systemic In aggregate, the data to date on compari- sons of double versus triple therapy demonstrate that double therapy significantly reduces the risk of bleeding without a signal of harm with re- gard to stent thrombosis in clinical trials that en- rolled both patients with stable ischemic disease and patients with ACS.


Notably, the study was not powered to evaluate risk of stent thrombosis or systemic In aggregate, the data to date on compari- sons of double versus triple therapy demonstrate that double therapy significantly reduces the risk of bleeding without a signal of harm with re- gard to stent thrombosis in clinical trials that en- rolled both patients with stable ischemic disease and patients with ACS. With regard to the anti- thrombotic dosages studied, only the RE-DUAL PCI trial and WOEST trials studied antithrombotic dosages known to reduce the risk of systemic CLINICAL STATEMENTS AND GUIDELINES The ongoing AU- GUSTUS (A Study of Apixaban in Patients With Atrial Fibrillation, not Caused by a Heart Valve Problem, who are at Risk for Thrombosis due to Having had a Recent Coronary Event, Such as a Heart Attack or a Procedure to Open the Vessels of the Heart) trial is an open-label 2 2 factorial RCT to evaluate the safety of apixaban versus vi- tamin K antagonist and aspirin versus aspirin pla- cebo in patients with AF and ACS or PCI.S7.4-24 The ENTRUST-AF-PCI (Edoxaban Treatment Versus Vi- tamin K Antagonist in Patients With Atrial Fibril- lation Undergoing Percutaneous Coronary Inter- vention) is an ongoing trial evaluating edoxaban treatment versus vitamin K antagonist treatment in patients with AF undergoing PCI.S7.4-25 These trials will provide further evidence on treatment approaches designed to mitigate bleeding while reducing the risks of stent thrombosis and sys- temic thromboembolism. 8. The ISAR-TRIPLE (Triple Therapy in Patients on Oral Anticoagulation After Drug Eluting Stent was a randomized, open- label trial of patients receiving anticoagulation who underwent PCI with drug-eluting stents. Patients received concomitant anticoagulant and aspirin and were randomized to 6 weeks versus 6 months of clopidogrel.