There is no well-de ned reversal agent for bivalirudin, and patients with coagul- opathy and excessive bleeding require unusual in- terventions for hemorrhage control. Only anecdotal experience is available to address coagulopathy in cases of bivalirudin-related hemorrhage [68, 71]. Consensus suggests that a multifaceted approach offers the best chance of successful hemorrhage control for these pa- tients. Recombinant activated factor VII may be an important part of hemorrhage control but other in- terventions including modi ed ultra ltration, hemodialysis, and clotting factor replacement are also advocated [71]. References 1. Stoney WS. Evolution of cardiopulmonary bypass. Circu- lation 2009;119:2844 53. 2. Ferraris VA. Heroes and evidence. J Thorac Cardiovasc Surg 2002;124:11 3. 3. Bull BS, Korpman RA, Huse WM, Briggs BD. Heparin therapy during extracorporeal circulation. I. Problems inherent in existing heparin protocols. J Thorac Cardiovasc Surg 1975;69:674 84. 4. Young JA, Kisker CT, Doty DB. Adequate anticoagulation during cardiopulmonary bypass determined by activated clotting time and the appearance of brin monomer. Ann Thorac Surg 1978;26:231 40. 5. Na S. Stabilized infective endocarditis and altered heparin responsiveness during cardiopulmonary bypass. World J Surg 2009;33:1862 7. 6. Garvin S, FitzGerald DC, Despotis G, Shekar P, Body SC. Heparin concentration-based anticoagulation for cardiac surgery fails to reliably predict heparin bolus dose re- quirements. Anesth Analg 2010;111:849 55. 7. Grima C. The effects of intermittent prebypass heparin dosing in patients undergoing coronary artery bypass grafting. Perfusion 2003;18:283 9. 8. Neema P, Sinha P, Rathod R. Activated clotting time during cardiopulmonary bypass: is repetition necessary during open heart surgery? Asian Cardiovasc Thorac Ann 2004;12: 47 52. 9. Shore-Lesserson L. Evidence based coagulation monitors: heparin monitoring, thromboelastography, and platelet function. Semin Cardiothorac Vasc Anesth 2005;9:41 52. 10.


Shore-Lesserson L. Evidence based coagulation monitors: heparin monitoring, thromboelastography, and platelet function. Semin Cardiothorac Vasc Anesth 2005;9:41 52. 10. Machin D, Devine P. The effect of temperature and apro- tinin during cardiopulmonary bypass on three different methods of activated clotting time measurement. J Extra Corpor Technol 2005;37:265 71. 11. Leyvi G, Shore-Lesserson L, Harrington D, Vela-Cantos F, Hossain S. An investigation of a new activated clotting time MAX-ACT in patients undergoing extracorporeal circula- tion. Anesth Analg 2001;92:578 83. 12. Koster A, Fischer T, Praus M, et al. Hemostatic activation and in ammatory response during cardiopulmonary bypass: impact of heparin management. Anesthesiology 2002;97:837 41. 13. Despotis GJ, Joist JH, Hogue CW, et al. The impact of heparin concentration and activated clotting time moni- toring on blood conservation. A prospective, randomized evaluation in patients undergoing cardiac operation. J Thorac Cardiovasc Surg 1995;110:46 54. 14. Despotis GJ, Joist JH, Hogue CW, et al. More effective suppression of hemostatic system activation in patients undergoing cardiac surgery by heparin dosing based on heparin blood concentrations rather than ACT. Thromb Haemost 1996;76:902 8. 15. Pappalardo F, Franco A, Crescenzi G, De Simone F, Torracca L, Zangrillo A. Anticoagulation management in patients undergoing open heart surgery by activated clot- ting time and whole blood heparin concentration. Perfusion 2006;21:285 90. 16. Hofmann B, Bushnaq H, Kraus FB, et al. Immediate effects of individualized heparin and protamine management on hemostatic activation and platelet function in adult patients undergoing cardiac surgery with tranexamic acid anti- brinolytic therapy. Perfusion 2013;28:412 8. 17. Newsome J, Stipanovich K, Flaherty S. Comparison of heparin administration using the Rapidpoint Coag and Hepcon HMS. J Extra Corpor Technol 2004;36:139 44. 18.


Newsome J, Stipanovich K, Flaherty S. Comparison of heparin administration using the Rapidpoint Coag and Hepcon HMS. J Extra Corpor Technol 2004;36:139 44. 18. Hansen R, Koster A, Kukucka M, Mertzlufft F, Kuppe H. A quick anti-Xa-activity-based whole blood coagulation assay for monitoring unfractionated heparin during Ann Thorac Surg 2018;105:650 62 ANTICOAGULATION DURING CARDIOPULMONARY BYPASS REPORT cardiopulmonary bypass: a pilot investigation. Anesth Analg 2000;91:533 8. 19. Hellstern P, Bach J, Simon M, Saggau W. Heparin moni- toring during cardiopulmonary bypass surgery using the one-step point-of-care whole blood anti-factor-Xa clotting assay Heptest-POC-Hi. J Extra Corpor Technol 2007;39: 81 6. 20. Gravlee GP, Haddon WS, Rothberger HK, et al. Heparin dosing and monitoring for cardiopulmonary bypass. A comparison of techniques with measurement of subclinical plasma coagulation. J Thorac Cardiovasc Surg 1990;99: 518 27. 21. Gravlee GP, Rogers AT, Dudas LM, et al. Heparin man- agement protocol for cardiopulmonary bypass in uences postoperative heparin rebound but not bleeding. Anesthe- siology 1992;76:393 401. 22. Ichikawa J, Kodaka M, Nishiyama K, Hirasaki Y, Ozaki M, Komori M. Reappearance of circulating heparin in whole blood heparin concentration-based management does not correlate with postoperative bleeding after cardiac surgery. J Cardiothorac Vasc Anesth 2014;28:1015 9. 23. Bosch YP, Ganushchak YM, de Jong DS. Comparison of ACT point-of-care measurements: repeatability and agree- ment. Perfusion 2006;21:27 31. 24. Wallock M, Jeske WP, Bakhos M, Walenga JM. Evaluation of a new point of care heparin test for cardiopulmonary bypass: the TAS heparin management test. Perfusion 2001;16:147 53. 25. Leyvi G, Zhuravlev I, Inyang A, et al. Arterial versus venous sampling for activated coagulation time measurements during cardiac surgery: a comparative study. J Cardiothorac Vasc Anesth 2004;18:573 80. 26. Searles B, Nasrallah F, Darling E, Yarcusko S. How does the age of a blood sample affect its activated clotting time?


Searles B, Nasrallah F, Darling E, Yarcusko S. How does the age of a blood sample affect its activated clotting time? Comparison of eight different devices. J Extra Corpor Technol 2002;34:175 7. 27. Welsby IJ, McDonnell E, El-Moalem H, Stafford-Smith M, Toffaletti JG. Activated clotting time systems vary in pre- cision and bias and are not interchangeable when following heparin management protocols during cardiopulmonary bypass. J Clin Monit Comput 2002;17:287 92. 28. Raymond PD, Ray MJ, Callen SN, Marsh NA. Heparin monitoring during cardiac surgery. Part 2: calculating the overestimation of heparin by the activated clotting time. Perfusion 2003;18:277 81. 29. Patteril M, Stafford-Smith M, Toffaletti JG, Bute BP, Milano CA, Welsby IJ. Changing systems for measuring activated clotting times: impact on the clinical practice of heparin anticoagulation during cardiac surgery. Clin Chim Acta 2005;356:218 24. 30. Chavez JJ, Foley DE, Snider CC, et al. A novel thrombe- lastograph tissue factor/kaolin assay of activated clotting times for monitoring heparin anticoagulation during car- diopulmonary bypass. Anesth Analg 2004;99:1290 4. 31. Ganter MT, Monn A, Tavakoli R, et al. Monitoring activated clotting time for combined heparin and aprotinin applica- tion: in vivo evaluation of a new aprotinin-insensitive test using Sonoclot. Eur J Cardiothorac Surg 2006;30:278 84. 32. Ganter MT, Monn A, Tavakoli R, Klaghofer R, Zollinger A, Hofer CK. Kaolin-based activated coagulation time measured by Sonoclot in patients undergoing cardiopul- monary bypass. J Cardiothorac Vasc Anesth 2007;21:524 8. 33. Watson H, Davidson S, Keeling D, Haemostasis and Thrombosis Task Force of the British Committee for Stan- dards in Haematology. Guidelines on the diagnosis and management of heparin-induced thrombocytopenia: sec- ond edition. Br J Haematol 2012;159:528 40. 34. Prechel MM, Walenga JM. Emphasis on the role of PF4 in the incidence, pathophysiology and treatment of heparin induced thrombocytopenia. Thromb J 2013;11:7. 35.


Emphasis on the role of PF4 in the incidence, pathophysiology and treatment of heparin induced thrombocytopenia. Thromb J 2013;11:7. 35. Bircher AJ, Harr T, Hohenstein L, Tsakiris DA. Hypersen- sitivity reactions to anticoagulant drugs: diagnosis and management options. Allergy 2006;61:1432 40. 36. Centers for Disease Control. Acute allergic-type reactions among patients undergoing hemodialysis multiple states, 2007 2008. MMWR Morb Mortal Wkly Rep 2008;57:124 5. 37. Greinacher A. Heparin-induced thrombocytopenia. N Engl J Med 2015;373:252 61. 38. Warkentin TE. Clinical picture of heparin-induced throm- bocytopenia (HIT) and its differentiation from non-HIT thrombocytopenia. Thromb Haemost 2016;116:813 22. 39. Kerendi F, Thourani VH, Puskas JD, et al. Impact of heparin-induced thrombocytopenia on postoperative out- comes after cardiac surgery. Ann Thorac Surg 2007;84: 1548 55. 40. Bennett-Guerrero E, Slaughter TF, White WD, et al. Pre- operative anti-PF4/heparin antibody level predicts adverse outcome after cardiac surgery. J Thorac Cardiovasc Surg 2005;130:1567 72. 41. Kress DC, Aronson S, McDonald ML, et al. Positive heparin-platelet factor 4 antibody complex and cardiac surgical outcomes. Ann Thorac Surg 2007;83:1737 43. 42. Stribling WK, Slaughter TF, Houle TT, Sane DC. Beyond the platelet count: heparin antibodies as independent risk predictors. Am Heart J 2007;153:900 6. 43. Linkins LA, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced thrombocytopenia: antith- rombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141(Suppl):e495 530. 44. Selleng S, Haneya A, Hirt S, Selleng K, Schmid C, Greinacher A. Management of anticoagulation in patients with subacute heparin-induced thrombocytopenia sched- uled for heart transplantation. Blood 2008;112:4024 7. 45. Warkentin TE, Sheppard JA. Serological investigation of patients with a previous history of heparin-induced thrombocytopenia who are reexposed to heparin. Blood 2014;123:2485 93. 46. Warkentin TE, Greinacher A, Koster A, Lincoff AM.


Blood 2014;123:2485 93. 46. Warkentin TE, Greinacher A, Koster A, Lincoff AM. Treatment and prevention of heparin-induced thrombocy- topenia: American College of Chest Physicians evidence- based clinical practice guidelines (8th edition). Chest 2008;133(Suppl):340 80. 47. Lubenow N, Kempf R, Eichner A, Eichler P, Carlsson LE, Greinacher A. Heparin-induced thrombocytopenia: tem- poral pattern of thrombocytopenia in relation to initial use or reexposure to heparin. Chest 2002;122:37 42. 48. Warkentin TE, Kelton JG. A 14-year study of heparin- induced thrombocytopenia. Am J Med 1996;101:502 7. 49. Nuttall GA, Oliver WC, Santrach PJ, et al. Patients with a history of type II heparin-induced thrombocytopenia with thrombosis requiring cardiac surgery with cardiopulmo- nary bypass: a prospective observational case series. Anesth Analg 2003;96:344 50. 50. Potzsch B, Klovekorn WP, Madlener K. Use of heparin during cardiopulmonary bypass in patients with a history of heparin-induced thrombocytopenia. N Engl J Med 2000;343: 515. 51. Warkentin TE, Arnold DM, Nazi I, Kelton JG. The platelet serotonin-release assay. Am J Hematol 2015;90:564 72. 52. Warkentin TE. Heparin-induced thrombocytopenia in crit- ically ill patients. Semin Thromb Hemost 2015;41:49 60. 53. Piednoir P, Allou N, Provenchere S, et al. Heparin-induced thrombocytopenia after cardiac surgery: an observational study of 1,722 patients. J Cardiothorac Vasc Anesth 2012;26: 585 90. 54. Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A. Evaluation of pretest clinical score (4 T s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost 2006;4:759 65. 55. Lillo-Le Louet A, Boutouyrie P, Alhenc-Gelas M, et al. Diagnostic score for heparin-induced thrombocytopenia after cardiopulmonary bypass. J Thromb Haemost 2004;2: 1882 8. 56. Cuker A, Arepally G, Crowther MA, et al.


J Thromb Haemost 2004;2: 1882 8. 56. Cuker A, Arepally G, Crowther MA, et al. The HIT expert probability (HEP) score: a novel pre-test probability model 660 Ann Thorac Surg ANTICOAGULATION DURING CARDIOPULMONARY BYPASS 2018;105:650 62 REPORT for heparin-induced thrombocytopenia based on broad expert opinion. J Thromb Haemost 2010;8:2642 50. 57. Cuker A, Gimotty PA, Crowther MA, Warkentin TE. Pre- dictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood 2012;120:4160 7. 58. Warkentin TE, Kelton JG. Temporal aspects of heparin- induced thrombocytopenia. N Engl J Med 2001;344:1286 92. 59. Warkentin TE, Sheppard JA, Horsewood P, Simpson PJ, Moore JC, Kelton JG. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood 2000;96:1703 8. 60. Pouplard C, May MA, Regina S, Marchand M, Fusciardi J, Gruel Y. Changes in platelet count after cardiac surgery can effectively predict the development of pathogenic heparin- dependent antibodies. Br J Haematol 2005;128:837 41. 61. Warkentin TE, Greinacher A. Heparin-induced thrombo- cytopenia: recognition, treatment, and prevention: the sev- enth ACCP conference on antithrombotic and thrombolytic therapy. Chest 2004;126(Suppl):311 37. 62. Berkun Y, Haviv YS, Schwartz LB, Shalit M. Heparin- induced recurrent anaphylaxis. Clin Exp Allergy 2004;34: 1916 8. 63. Grims RH, Weger W, Reiter H, Arbab E, Kranke B, Aberer W. Delayed-type hypersensitivity to low molecular weight heparins and heparinoids: cross-reactivity does not depend on molecular weight. Br J Dermatol 2007;157:514 7. 64. Jappe U. Allergy to heparins and anticoagulants with a similar pharmacological pro le: an update. Blood Coagul Fibrinolysis 2006;17:605 13. 65. Koster A, Spiess B, Chew DP, et al. Effectiveness of biva- lirudin as a replacement for heparin during cardiopulmo- nary bypass in patients undergoing coronary artery bypass grafting. Am J Cardiol 2004;93:356 9. 66. Zucker ML, Koster A, Prats J, Laduca FM.


Am J Cardiol 2004;93:356 9. 66. Zucker ML, Koster A, Prats J, Laduca FM. Sensitivity of a modi ed ACT test to levels of bivalirudin used during cardiac surgery. J Extra Corpor Technol 2005;37:364 8. 67. Merry AF. Focus on thrombin: alternative anticoagulants. Semin Cardiothorac Vasc Anesth 2007;11:256 60. 68. Nagle EL, Tsu LV, Dager WE. Bivalirudin for anti- coagulation during hypothermic cardiopulmonary bypass and recombinant factor VIIa for iatrogenic coagulopathy. Ann Pharmacother 2011;45:e47. 69. Koster A, Dyke CM, Aldea G, et al. Bivalirudin during cardiopulmonary bypass in patients with previous or acute heparin-induced thrombocytopenia and heparin anti- bodies: results of the CHOOSE-ON trial. Ann Thorac Surg 2007;83:572 7. 70. Dyke CM, Smedira NG, Koster A, et al. A comparison of bivalirudin to heparin with protamine reversal in patients undergoing cardiac surgery with cardiopulmonary bypass: the EVOLUTION-ON study. J Thorac Cardiovasc Surg 2006;131:533 9. 71. Stratmann G, deSilva AM, Tseng EE, et al. Reversal of direct thrombin inhibition after cardiopulmonary bypass in a pa- tient with heparin-induced thrombocytopenia. Anesth Analg 2004;98:1635 9. 72. Koster A, Buz S, Krabatsch T, et al. Effect of modi ed ul- tra ltration on bivalirudin elimination and postoperative blood loss after on-pump coronary artery bypass grafting: assessment of different ltration strategies. J Card Surg 2008;23:655 8. 73. Schwartz J, Winters JL, Padmanabhan A, et al. Guidelines on the use of therapeutic apheresis in clinical practice- evidence-based approach from the Writing Committee of the American Society for Apheresis: the sixth special issue. J Clin Apher 2013;28:145 284. 74. Welsby IJ, Um J, Milano CA, Ortel TL, Arepally G. Plas- mapheresis and heparin reexposure as a management strategy for cardiac surgical patients with heparin-induced thrombocytopenia. Anesth Analg 2010;110:30 5. 75. Warkentin TE, Sheppard JA, Chu FV, Kapoor A, Crowther MA, Gangji A.


Warkentin TE, Sheppard JA, Chu FV, Kapoor A, Crowther MA, Gangji A. Plasma exchange to remove HIT antibodies: dissociation between enzyme-immunoassay and platelet activation test reactivities. Blood 2015;125: 195 8. 76. Addonizio VP, Fisher CA, Kappa JR, Ellison N. Prevention of heparin-induced thrombocytopenia during open heart surgery with iloprost (ZK36374). Surgery 1987;102:796 807. 77. Palatianos GM, Foroulis CN, Vassili MI, et al. Preoperative detection and management of immune heparin-induced thrombocytopenia in patients undergoing heart surgery with iloprost. J Thorac Cardiovasc Surg 2004;127:548 54. 78. Koster A, Kukucka M, Bach F, et al. Anticoagulation during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II and renal impairment using heparin and the platelet glycoprotein IIb-IIIa antagonist tiro ban. Anesthesiology 2001;94:245 51. 79. Tanigawa Y, Yamada T, Matsumoto K, Nakagawachi A, Torikai A, Sakaguchi Y. Non-recovery of ACT in a patient with heparin-induced thrombocytopenia type II during mitral valve replacement using argatroban anticoagulation. J Anesth 2013;27:951 5. 80. Genzen JR, Fareed J, Hoppensteadt D, et al. Prolonged elevation of plasma argatroban in a cardiac transplant pa- tient with a suspected history of heparin-induced throm- bocytopenia with thrombosis. Transfusion 2010;50:801 7. 81. Agarwal S, Ullom B, Al-Baghdadi Y, Okumura M. Chal- lenges encountered with argatroban anticoagulation during cardiopulmonary bypass. J Anaesthesiol Clin Pharmacol 2012;28:106 10. 82. Follis F, Filippone G, Montalbano G, et al. Argatroban as a substitute of heparin during cardiopulmonary bypass: a safe alternative? Interact Cardiovasc Thorac Surg 2010;10: 592 6. 83. Murphy GS, Marymont JH. Alternative anticoagulation management strategies for the patient with heparin- induced thrombocytopenia undergoing cardiac surgery. J Cardiothorac Vasc Anesth 2007;21:113 26. 84. Galeone A, Rotunno C, Guida P, et al. Monitoring incom- plete heparin reversal and heparin rebound after cardiac surgery. J Cardiothorac Vasc Anesth 2013;27:853 8. 85.


Monitoring incom- plete heparin reversal and heparin rebound after cardiac surgery. J Cardiothorac Vasc Anesth 2013;27:853 8. 85. Murray DJ, Brosnahan WJ, Pennell B, Kapalanski D, Weiler JM, Olson J. Heparin detection by the activated coagulation time: a comparison of the sensitivity of coagu- lation tests and heparin assays. J Cardiothorac Vasc Anesth 1997;11:24 8. 86. Guo Y, Tang J, Du L, et al. Protamine dosage based on two titrations reduces blood loss after valve replacement sur- gery: a prospective, double-blinded, randomized study. Can J Cardiol 2012;28:547 52. 87. Shigeta O, Kojima H, Hiramatsu Y, et al. Low-dose prot- amine based on heparin-protamine titration method re- duces platelet dysfunction after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1999;118:354 60. 88. Runge M, Moller CH, Steinbruchel DA. Increased accuracy in heparin and protamine administration decreases bleeding: a pilot study. J Extra Corpor Technol 2009;41:10 4. 89. Shore-Lesserson L, Reich DL, DePerio M. Heparin and protamine titration do not improve haemostasis in cardiac surgical patients. Can J Anaesth 1998;45:10 8. 90. Gundry SR, Drongowski RA, Coran AG, Kirsh MM, Klein MD. Failure of automated protamine titration to determine the protamine reversal dose of systemic heparin: comparison with other methods. Curr Surg 1986;43:110 2. 91. Wang J, Ma HP, Zheng H. Blood loss after cardiopulmonary bypass, standard versus titrated protamine: a meta-analysis. Neth J Med 2013;71:123 7. 92. Vonk AB, Veerhoek D, van den Brom CE, van Barneveld LJ, Boer C. Individualized heparin and protamine management improves rotational thromboelastometric parameters and postoperative hemostasis in valve surgery. J Cardiothorac Vasc Anesth 2014;28:235 41. 93.


Vonk AB, Veerhoek D, van den Brom CE, van Barneveld LJ, Boer C. Individualized heparin and protamine management improves rotational thromboelastometric parameters and postoperative hemostasis in valve surgery. J Cardiothorac Vasc Anesth 2014;28:235 41. 93. Koster A, Borgermann J, Gummert J, Rudloff M, Zittermann A, Schirmer U. Protamine overdose and its impact on coagulation, bleeding, and transfusions after Ann Thorac Surg 2018;105:650 62 ANTICOAGULATION DURING CARDIOPULMONARY BYPASS REPORT cardiopulmonary bypass: results of a randomized double- blind controlled pilot study. Clin Appl Thromb Hemost 2014;20:290 5. 94. Mochizuki T, Olson PJ, Szlam F, Ramsay JG, Levy JH. Protamine reversal of heparin affects platelet aggregation and activated clotting time after cardiopulmonary bypass. Anesth Analg 1998;87:781 5. 95. Carr ME, Carr SL. At high heparin concentrations, prot- amine concentrations which reverse heparin anticoagulant effects are insuf cient to reverse heparin anti-platelet ef- fects. Thromb Res 1994;75:617 30. 96. Dunning J, Versteegh M, Fabbri A, et al. Guideline on an- tiplatelet and anticoagulation management in cardiac sur- gery. Eur J Cardiothorac Surg 2008;34:73 92. 97. Martin P, Horkay F, Gupta NK, Gebitekin C, Walker DR. Heparin rebound phenomenon much ado about nothing? Blood Coagul Fibrinolysis 1992;3:187 91. 98. Taneja R, Marwaha G, Sinha P, et al. Elevated activated partial thromboplastin time does not correlate with heparin rebound following cardiac surgery. Can J Anaesth 2009;56: 489 96. 99. Teoh KH, Young E, Blackall MH, Roberts RS, Hirsh J. Can extra protamine eliminate heparin rebound following car- diopulmonary bypass surgery? J Thorac Cardiovasc Surg 2004;128:211 9. 100. Nybo M, Madsen JS. Serious anaphylactic reactions due to protamine sulfate: a systematic literature review. Basic Clin Pharmacol Toxicol 2008;103:192 6. 101. Boigner H, Lechner E, Brock H, Golej J, Trittenwein G. Life threatening cardiopulmonary failure in an infant following protamine reversal of heparin after cardiopulmonary bypass.


Boigner H, Lechner E, Brock H, Golej J, Trittenwein G. Life threatening cardiopulmonary failure in an infant following protamine reversal of heparin after cardiopulmonary bypass. Paediatr Anaesth 2001;11:729 32. 102. Kimmel SE, Sekeres M, Berlin JA, Ellison N. Mortality and adverse events after protamine administration in patients undergoing cardiopulmonary bypass. Anesth Analg 2002;94:1402 8. 103. Welsby IJ, Newman MF, Phillips-Bute B, Messier RH, Kakkis ED, Stafford-Smith M. Hemodynamic changes after protamine administration: association with mortality after coronary artery bypass surgery. Anesthesiology 2005;102: 308 14. 104. Kimmel SE, Sekeres MA, Berlin JA, Goldberg LR, Strom BL. Adverse events after protamine administration in patients undergoing cardiopulmonary bypass: risks and predictors of under-reporting. J Clin Epidemiol 1998;51:1 10. 105. Ford SA, Kam PC, Baldo BA, Fisher MM. Anaphylactic or anaphylactoid reactions in patients undergoing cardiac surgery. J Cardiothorac Vasc Anesth 2001;15:684 8. 106. Viaro F, Dalio MB, Evora PR. Catastrophic cardiovascular adverse reactions to protamine are nitric oxide/cyclic guanosine monophosphate dependent and endothelium mediated: should methylene blue be the treatment of choice? Chest 2002;122:1061 6. 107. Comunale ME, Maslow A, Robertson LK, Haering JM, Mashikian JS, Lowenstein E. Effect of site of venous prot- amine administration, previously alleged risk factors, and preoperative use of aspirin on acute protamine-induced pulmonary vasoconstriction. J Cardiothorac Vasc Anesth 2003;17:309 13. 108. Ocal A, Kiris I, Erdinc M, Peker O, Yavuz T, Ibrisim E. Ef- ciency of prostacyclin in the treatment of protamine- mediated right ventricular failure and acute pulmonary hypertension. Tohoku J Exp Med 2005;207:51 8. 109. Olinger GN, Becker RM, Bonchek LI. Noncardiogenic pul- monary edema and peripheral vascular collapse following cardiopulmonary bypass: rare protamine reaction? Ann Thorac Surg 1980;29:20 5. 110. Pretorius M, Scholl FG, McFarlane JA, Murphey LJ, Brown NJ.


Pretorius M, Scholl FG, McFarlane JA, Murphey LJ, Brown NJ. A pilot study indicating that bradykinin B2 re- ceptor antagonism attenuates protamine-related hypoten- sion after cardiopulmonary bypass. Clin Pharmacol Ther 2005;78:477 85. 111. Lee GM, Welsby IJ, Phillips-Bute B, Ortel TL, Arepally GM. High incidence of antibodies to protamine and protamine/ heparin complexes in patients undergoing cardiopulmo- nary bypass. Blood 2013;121:2828 35. 112. Bakchoul T, Zollner H, Amiral J, et al. Anti-protamine- heparin antibodies: incidence, clinical relevance, and path- ogenesis. Blood 2013;121:2821 7. 113. Vincent GM, Janowski M, Menlove R. Protamine allergy reactions during cardiac catheterization and cardiac sur- gery: risk in patients taking protamine-insulin preparations. Cathet Cardiovasc Diagn 1991;23:164 8. 114. Bernabei A, Gikakis N, Maione TE, et al. Reversal of heparin anticoagulation by recombinant platelet factor 4 and prot- amine sulfate in baboons during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1995;109:765 71. 115. Levy JH, Cormack JG, Morales A. Heparin neutralization by recombinant platelet factor 4 and protamine. Anesth Analg 1995;81:35 7. 116. Demma L, Levy JH. A case series of recombinant platelet factor 4 for heparin reversal after cardiopulmonary bypass. Anesth Analg 2012;115:1273 8. 117. Kikura M, Lee MK, Levy JH. Heparin neutralization with methylene blue, hexadimethrine, or vancomycin after car- diopulmonary bypass. Anesth Analg 1996;83:223 7. 118. Stafford-Smith M, Lefrak EA, Qazi AG, et al. Ef cacy and safety of heparinase I versus protamine in patients under- going coronary artery bypass grafting with and without cardiopulmonary bypass. Anesthesiology 2005;103:229 40. 662 Ann Thorac Surg ANTICOAGULATION DURING CARDIOPULMONARY BYPASS 2018;105:650 62 REPORT


Stable angina: management Clinical guideline NICE 2022. All rights reserved. Subject to Notice of rights (https://www.nice.org.uk/terms-and- conditions#notice-of-rights). Last updated 25 August 2016 Your responsibility The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals and practitioners are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or the people using their service. It is not mandatory to apply the recommendations, and the guideline does not override the responsibility to make decisions appropriate to the circumstances of the individual, in consultation with them and their families and carers or guardian. All problems (adverse events) related to a medicine or medical device used for treatment or in a procedure should be reported to the Medicines and Healthcare products Regulatory Agency using the Yellow Card Scheme. Local commissioners and providers of healthcare have a responsibility to enable the guideline to be applied when individual professionals and people using services wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with complying with those duties. Commissioners and providers have a responsibility to promote an environmentally sustainable health and care system and should assess and reduce the environmental impact of implementing NICE recommendations wherever possible.


Commissioners and providers have a responsibility to promote an environmentally sustainable health and care system and should assess and reduce the environmental impact of implementing NICE recommendations wherever possible. Contents Key priorities for implementation 6 Guidance 9 1.2 Information and support for people with stable angina 9 1.3 General principles for treating people with stable angina 10 1.4 Anti-anginal drug treatment 12 1.5 Investigation and revascularisation 15 1.7 Stable angina that has not responded to treatment 19 1.8 Cardiac syndrome X 19 Recommendations for research 21 1 Adding a newer anti-anginal drug to a calcium channel blocker 21 2 Management of stable angina in people with evidence of ischaemia on non-invasive functional testing 21 3 Early revascularisation strategy for people with angina and multivessel disease 22 4 Cardiac rehabilitation 23 5 Patient self-management plans 23 Finding more information and committee details 25 Update information 26 This guideline partially replaces TA73. This guideline is the basis of QS21 and QS181. Introduction Angina is pain or constricting discomfort that typically occurs in the front of the chest (but may radiate to the neck, shoulders, jaw or arms) and is brought on by physical exertion or emotional stress. Some people can have atypical symptoms, such as gastrointestinal discomfort, breathlessness or nausea. Angina is the main symptom of myocardial ischaemia and is usually caused by atherosclerotic obstructive coronary artery disease restricting blood flow and therefore oxygen delivery to the heart muscle. The Health Survey for England (2006) reported that around 8% of men and 3% of women aged between 55 and 64 years currently have or have had angina. The figures for men and women aged between 65 and 74 years are around 14% and 8% respectively. It is estimated that almost 2 million people in England currently have or have had angina.


It is estimated that almost 2 million people in England currently have or have had angina. Being diagnosed with angina can have a significant impact on a person's quality of life, restricting daily work and leisure activities. Stable angina is a chronic medical condition with a low but appreciable incidence of acute coronary events and increased mortality. The aim of management is to stop or minimise symptoms, and to improve quality of life and long-term morbidity and mortality. Management options include lifestyle advice, drug treatment and revascularisation using percutaneous or surgical techniques. Analysis of the comparative efficacy of different treatments for people with stable angina is difficult because of the advances in drug treatment and revascularisation strategies over several decades. Trials of drug treatment versus coronary artery bypass surgery were carried out more than 25 years ago and showed a survival advantage with surgery in patients with severe coronary artery disease. Statins and other secondary prevention treatments were not used when the trials were carried out and these treatments have a significant effect on morbidity and mortality. Percutaneous revascularisation techniques have developed, from balloon angioplasty to bare metal stents and drug eluting stents and each is associated with reduced rates of repeat revascularisation compared with the previous technique. All trials, including trials of revascularisation strategies, have been limited to people considered suitable for the intervention rather than being representative of the whole population with angina. The recommendations in this guideline relate only to people with a diagnosis of stable angina. Coronary artery disease can also present as acute coronary syndromes, such as unstable angina or myocardial infarction. The NICE guideline on recent-onset chest pain of suspected cardiac arrest origin, covers the diagnosis of stable angina and should be read in conjunction with this guideline.


The NICE guideline on recent-onset chest pain of suspected cardiac arrest origin, covers the diagnosis of stable angina and should be read in conjunction with this guideline. The guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients. This guideline recommends some drugs for indications for which they do not have a UK marketing authorisation at the date of publication, if there is good evidence to support that use. Where recommendations have been made for the use of drugs outside their licensed indications ('off-label use'), these drugs are marked with a footnote in the recommendations. Key priorities for implementation The following recommendations have been identified as priorities for implementation. Explore and address issues according to the person's needs, which may include: self-management skills such as pacing their activities and goal setting concerns about the impact of stress, anxiety or depression on angina advice about physical exertion including sexual activity. Offer people optimal drug treatment for the initial management of stable angina. Optimal drug treatment consists of one or two anti-anginal drugs as necessary plus drugs for secondary prevention of cardiovascular disease. Consider revascularisation (coronary artery bypass graft [CABG] or percutaneous coronary intervention [PCI]) for people with stable angina whose symptoms are not satisfactorily controlled with optimal medical treatment. When either procedure would be appropriate, explain to the person the risks and benefits of PCI and CABG for people with anatomically less complex disease whose symptoms are not satisfactorily controlled with optimal medical treatment. If the person does not express a preference, take account of the evidence that suggests that PCI may be the more cost-effective procedure in selecting the course of treatment.


If the person does not express a preference, take account of the evidence that suggests that PCI may be the more cost-effective procedure in selecting the course of treatment. When either procedure would be appropriate, take into account the potential survival advantage of CABG over PCI for people with multivessel disease whose symptoms are not satisfactorily controlled with optimal medical treatment and who: have diabetes or are over 65 years or have anatomically complex three-vessel disease, with or without involvement of the left main stem. Consider the relative risks and benefits of CABG and PCI for people with stable angina using a systematic approach to assess the severity and complexity of the person's coronary disease, in addition to other relevant clinical factors and comorbidities. Ensure that there is a regular multidisciplinary team meeting to discuss the risks and benefits of continuing drug treatment or the revascularisation strategy (CABG or PCI) for people with stable angina. The team should include cardiac surgeons and interventional cardiologists. Treatment strategy should be discussed for the following people, including but not limited to: people with left main stem or anatomically complex three-vessel disease people in whom there is doubt about the best method of revascularisation because of the complexity of coronary anatomy, the extent of stenting required or other relevant clinical factors and comorbidities. Ensure people with stable angina receive balanced information and have the opportunity to discuss the benefits, limitations and risks of continuing drug treatment, CABG and PCI to help them make an informed decision about their treatment. When either revascularisation procedure is appropriate, explain to the person: The main purpose of revascularisation is to improve the symptoms of stable angina. CABG and PCI are effective in relieving symptoms.


When either revascularisation procedure is appropriate, explain to the person: The main purpose of revascularisation is to improve the symptoms of stable angina. CABG and PCI are effective in relieving symptoms. Repeat revascularisation may be necessary after either CABG or PCI and the rate is lower after CABG. Stroke is uncommon after either CABG or PCI, and the incidence is similar between the two procedures. There is a potential survival advantage with CABG for some people with multivessel disease. Discuss the following with people whose symptoms are satisfactorily controlled with optimal medical treatment: their prognosis without further investigation the likelihood of having left main stem disease or proximal three-vessel disease the availability of CABG to improve the prognosis in a subgroup of people with left main stem or proximal three-vessel disease the process and risks of investigation the benefits and risks of CABG, including the potential survival gain. Guidance People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. Recommendations 1.5.2 and 1.5.12 partially update recommendation 1.2 of the NICE technology appraisal guidance on myocardial perfusion scintigraphy for the diagnosis and management of angina and myocardial infarction. The following guidance is for people who have a diagnosis of stable angina and is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance. 1.1.1 Diagnose stable angina according to the NICE guideline on recent-onset chest pain of suspected cardiac origin.


1.1.1 Diagnose stable angina according to the NICE guideline on recent-onset chest pain of suspected cardiac origin. Diagnose and manage unstable angina and NSTEMI according to the NICE guidelines on recent-onset chest pain of suspected cardiac origin, unstable angina and NSTEMI and acute coronary syndromes. 1.2 Information and support for people with stable angina 1.2.1 Clearly explain stable angina to the person, including factors that can provoke angina (for example, exertion, emotional stress, exposure to cold, eating a heavy meal) and its long-term course and management. When relevant, involve the person's family or carers in the discussion. 1.2.2 Encourage the person with stable angina to ask questions about their angina and its treatment. Provide opportunities for them to voice their concerns and fears. 1.2.3 Discuss the person's, and if appropriate, their family or carer's ideas, concerns and expectations about their condition, prognosis and treatment. Explore and address any misconceptions about stable angina and its implications for daily activities, heart attack risk and life expectancy. 1.2.4 Advise the person with stable angina to seek professional help if there is a sudden worsening in the frequency or severity of their angina. 1.2.5 Discuss with the person the purpose and any risks and benefits of their treatment. 1.2.6 Assess the person's need for lifestyle advice (for example about exercise, stopping smoking, diet and weight control) and psychological support, and offer interventions as necessary. 1.2.7 Explore and address issues according to the person's needs, which may include: self-management skills such as pacing their activities and goal setting concerns about the impact of stress, anxiety or depression on angina advice about physical exertion including sexual activity. 1.3 General principles for treating people with stable angina 1.3.1 Do not exclude people with stable angina from treatment based on their age alone.


1.3 General principles for treating people with stable angina 1.3.1 Do not exclude people with stable angina from treatment based on their age alone. 1.3.2 Do not investigate or treat symptoms of stable angina differently in men and women or in different ethnic groups. Preventing and treating episodes of angina 1.3.3 Offer a short-acting nitrate for preventing and treating episodes of angina. Advise people with stable angina: how to administer the short-acting nitrate to use it immediately before any planned exercise or exertion that side effects such as flushing, headache and light-headedness may occur to sit down or find something to hold on to if feeling light-headed. 1.3.4 When a short-acting nitrate is being used to treat episodes of angina, advise people: to repeat the dose after 5 minutes if the pain has not gone to call an emergency ambulance if the pain has not gone 5 minutes after taking a second dose. Drugs for secondary prevention of cardiovascular disease 1.3.5 Consider aspirin 75 mg daily for people with stable angina, taking into account the risk of bleeding and comorbidities. 1.3.6 Consider angiotensin-converting enzyme (ACE) inhibitors for people with stable angina and diabetes. Offer or continue ACE inhibitors for other conditions, in line with relevant NICE guidance. 1.3.7 Offer statin treatment in line with the NICE guideline on lipid modification. 1.3.8 Offer treatment for high blood pressure in line with the NICE guideline on hypertension. Dietary supplements 1.3.9 Do not offer vitamin or fish oil supplements to treat stable angina. Inform people that there is no evidence that they help stable angina. 1.4 Anti-anginal drug treatment General recommendations 1.4.1 Offer people optimal drug treatment for the initial management of stable angina.


1.4 Anti-anginal drug treatment General recommendations 1.4.1 Offer people optimal drug treatment for the initial management of stable angina. Optimal drug treatment consists of one or two anti-anginal drugs as necessary plus drugs for secondary prevention of cardiovascular disease. 1.4.2 Advise people that the aim of anti-anginal drug treatment is to prevent episodes of angina and the aim of secondary prevention treatment is to prevent cardiovascular events such as heart attack and stroke. 1.4.3 Discuss how side effects of drug treatment might affect the person's daily activities and explain why it is important to take drug treatment regularly. 1.4.4 Patients differ in the type and amount of information they need and want. Therefore the provision of information should be individualised and is likely to include, but not be limited to: what the medicine is how the medicine is likely to affect their condition (that is, its benefits) likely or significant adverse effects and what to do if they think they are experiencing them how to use the medicine what to do if they miss a dose whether further courses of the medicine will be needed after the first prescription how to get further supplies of medicines. [This recommendation is from the NICE guideline on medicines adherence.] 1.4.5 Review the person's response to treatment, including any side effects, 2 to 4 weeks after starting or changing drug treatment. 1.4.6 Titrate the drug dosage against the person's symptoms up to the maximum tolerable dosage. Drugs for treating stable angina 1.4.7 Offer either a beta blocker or a calcium channel blocker as first-line treatment for stable angina. Decide which drug to use based on comorbidities, contraindications and the person's preference.


Decide which drug to use based on comorbidities, contraindications and the person's preference. 1.4.8 If the person cannot tolerate the beta blocker or calcium channel blocker, consider switching to the other option (calcium channel blocker or beta blocker). 1.4.9 If the person's symptoms are not satisfactorily controlled on a beta blocker or a calcium channel blocker, consider either switching to the other option or using a combination of the two. When combining a calcium channel blocker with a beta blocker, use a dihydropyridine calcium channel blocker, for example, slow release nifedipine, amlodipine or felodipine. 1.4.10 Do not routinely offer anti-anginal drugs other than beta blockers or calcium channel blockers as first-line treatment for stable angina. 1.4.11 If the person cannot tolerate beta blockers and calcium channel blockers or both are contraindicated, consider monotherapy with one of the following drugs: a long-acting nitrate or ivabradine or nicorandil or ranolazine. Decide which drug to use based on comorbidities, contraindications, the person's preference and drug costs. Since this guidance was produced, the Medicines and Healthcare products Regulatory Agency (MHRA) have published new advice about safety concerns related to ivabradine (June 2014 and December 2014) and nicorandil (January 2016). 1.4.12 For people on beta blocker or calcium channel blocker monotherapy whose symptoms are not controlled and the other option (calcium channel blocker or beta blocker) is contraindicated or not tolerated, consider one of the following as an additional drug: a long-acting nitrate or ivabradine or nicorandil or ranolazine. Decide which drug to use based on comorbidities, contraindications, the person's preference and drug costs. Since this guidance was produced, the Medicines and Healthcare products Regulatory Agency (MHRA) have published new advice about safety concerns related to ivabradine (June 2014 and December 2014) and nicorandil (January 2016).


Since this guidance was produced, the Medicines and Healthcare products Regulatory Agency (MHRA) have published new advice about safety concerns related to ivabradine (June 2014 and December 2014) and nicorandil (January 2016). When combining ivabradine with a calcium channel blocker, use a dihydropyridine calcium channel blocker, for example, slow release nifedipine, amlodipine, or felodipine. 1.4.13 Do not offer a third anti-anginal drug to people whose stable angina is controlled with two anti-anginal drugs. 1.4.14 Consider adding a third anti-anginal drug only when: the person's symptoms are not satisfactorily controlled with two anti-anginal drugs and the person is waiting for revascularisation or revascularisation is not considered appropriate or acceptable. Decide which drug to use based on comorbidities, contraindications, the person's preference and drug costs. 1.5 Investigation and revascularisation People with stable angina whose symptoms are not satisfactorily controlled with optimal medical treatment 1.5.1 Consider revascularisation (coronary artery bypass graft [CABG] or percutaneous coronary intervention [PCI]) for people with stable angina whose symptoms are not satisfactorily controlled with optimal medical treatment. 1.5.2 Offer coronary angiography to guide treatment strategy for people with stable angina whose symptoms are not satisfactorily controlled with optimal medical treatment. Additional non-invasive or invasive functional testing may be required to evaluate angiographic findings and guide treatment decisions. [This recommendation partially updates recommendation 1.2 of the NICE technology appraisal guidance on myocardial perfusion scintigraphy for the diagnosis and management of angina and myocardial infarction.] 1.5.3 Offer CABG to people with stable angina and suitable coronary anatomy when: their symptoms are not satisfactorily controlled with optimal medical treatment and revascularisation is considered appropriate and PCI is not appropriate.


1.5.3 Offer CABG to people with stable angina and suitable coronary anatomy when: their symptoms are not satisfactorily controlled with optimal medical treatment and revascularisation is considered appropriate and PCI is not appropriate. 1.5.4 Offer PCI to people with stable angina and suitable coronary anatomy when: their symptoms are not satisfactorily controlled with optimal medical treatment and revascularisation is considered appropriate and CABG is not appropriate. 1.5.5 When either procedure would be appropriate, explain to the person the risks and benefits of PCI and CABG for people with anatomically less complex disease whose symptoms are not satisfactorily controlled with optimal medical treatment. If the person does not express a preference, take account of the evidence that suggests that PCI may be the more cost-effective procedure in selecting the course of treatment. 1.5.6 When either procedure would be appropriate, take into account the potential survival advantage of CABG over PCI for people with multivessel disease whose symptoms are not satisfactorily controlled with optimal medical treatment and who: have diabetes or are over 65 years or have anatomically complex three-vessel disease, with or without involvement of the left main stem. 1.5.7 Consider the relative risks and benefits of CABG and PCI for people with stable angina using a systematic approach to assess the severity and complexity of the person's coronary disease, in addition to other relevant clinical factors and comorbidities. 1.5.8 Ensure that there is a regular multidisciplinary team meeting to discuss the risks and benefits of continuing drug treatment or revascularisation strategy (CABG or PCI) for people with stable angina. The team should include cardiac surgeons and interventional cardiologists.


1.5.8 Ensure that there is a regular multidisciplinary team meeting to discuss the risks and benefits of continuing drug treatment or revascularisation strategy (CABG or PCI) for people with stable angina. The team should include cardiac surgeons and interventional cardiologists. Treatment strategy should be discussed for the following people, including but not limited to: people with left main stem or anatomically complex three-vessel disease people in whom there is doubt about the best method of revascularisation because of the complexity of the coronary anatomy, the extent of stenting required or other relevant clinical factors and comorbidities. 1.5.9 Ensure people with stable angina receive balanced information and have the opportunity to discuss the benefits, limitations and risks of continuing drug treatment, CABG and PCI to help them make an informed decision about their treatment. When either revascularisation procedure is appropriate, explain to the person: The main purpose of revascularisation is to improve the symptoms of stable angina. CABG and PCI are effective in relieving symptoms. Repeat revascularisation may be necessary after either CABG or PCI and the rate is lower after CABG. Stroke is uncommon after either CABG or PCI, and the incidence is similar between the two procedures. There is a potential survival advantage with CABG for some people with multivessel disease. 1.5.10 Inform the person about the practical aspects of CABG and PCI. Include information about: vein and/or artery harvesting likely length of hospital stay recovery time drug treatment after the procedure.


Include information about: vein and/or artery harvesting likely length of hospital stay recovery time drug treatment after the procedure. People with stable angina whose symptoms are satisfactorily controlled with optimal medical treatment 1.5.11 Discuss the following with people whose symptoms are satisfactorily controlled with optimal medical treatment: their prognosis without further investigation the likelihood of having left main stem disease or proximal three-vessel disease the availability of CABG to improve the prognosis in a subgroup of people with left main stem or proximal three-vessel disease the process and risks of investigation the benefits and risks of CABG, including the potential survival gain. 1.5.12 After discussion (see 1.5.11) with people whose symptoms are satisfactorily controlled with optimal medical treatment, consider a functional or non-invasive anatomical test to identify people who might gain a survival benefit from surgery. Functional or anatomical test results may already be available from diagnostic assessment. [This recommendation partially updates recommendation 1.2 of the NICE technology appraisal guidance on myocardial perfusion scintigraphy for the diagnosis and management of angina and myocardial infarction.] 1.5.13 After discussion (see 1.5.11) with people whose symptoms are satisfactorily controlled with optimal medical treatment, consider coronary angiography when: functional testing indicates extensive ischaemia or non-invasive anatomical testing indicates the likelihood of left main stem or proximal three-vessel disease and revascularisation is acceptable and appropriate. 1.5.14 Consider CABG for people with stable angina and suitable coronary anatomy whose symptoms are satisfactorily controlled with optimal medical treatment, but coronary angiography indicates left main stem disease or proximal three-vessel disease. 1.6 Pain interventions 1.6.1 Do not offer the following interventions to manage stable angina: transcutaneous electrical nerve stimulation (TENS) enhanced external counterpulsation (EECP) acupuncture.


1.6 Pain interventions 1.6.1 Do not offer the following interventions to manage stable angina: transcutaneous electrical nerve stimulation (TENS) enhanced external counterpulsation (EECP) acupuncture. 1.7 Stable angina that has not responded to treatment 1.7.1 Offer people whose stable angina has not responded to drug treatment and/or revascularisation comprehensive re-evaluation and advice, which may include: exploring the person's understanding of their condition exploring the impact of symptoms on the person's quality of life reviewing the diagnosis and considering non-ischaemic causes of pain reviewing drug treatment and considering future drug treatment and revascularisation options acknowledging the limitations of future treatment explaining how the person can manage the pain themselves specific attention to the role of psychological factors in pain development of skills to modify cognitions and behaviours associated with pain. 1.8 Cardiac syndrome X 1.8.1 In people with angiographically normal coronary arteries and continuing anginal symptoms, consider a diagnosis of cardiac syndrome X. 1.8.2 Continue drug treatment for stable angina only if it improves the symptoms of the person with suspected cardiac syndrome X. 1.8.3 Do not routinely offer drugs for the secondary prevention of cardiovascular disease to people with suspected cardiac syndrome X. Recommendations for research The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. 1 Adding a newer anti-anginal drug to a calcium channel blocker What is the clinical and cost effectiveness of adding a newer anti-anginal drug (nicorandil, ivabradine or ranolazine) to a calcium channel blocker for treating stable angina? Why this is important We do not know the long-term clinical and cost effectiveness of adding a newer anti- anginal drug to a calcium channel blocker in people with stable angina.


Why this is important We do not know the long-term clinical and cost effectiveness of adding a newer anti- anginal drug to a calcium channel blocker in people with stable angina. We propose a double-blind placebo-controlled randomised trial comparing the addition of a newer anti- anginal drug to a calcium channel blocker with a calcium channel blocker alone in people with stable angina whose symptoms are not being controlled. Endpoints would include symptom severity, quality of life, long-term morbidity and mortality, and cost effectiveness. The results of the trial would influence clinical practice and inform future updates of key recommendations in this guideline. 2 Management of stable angina in people with evidence of ischaemia on non-invasive functional testing Do people with stable angina and evidence of reversible ischaemia on non-invasive functional testing who are on optimal drug treatment benefit from routine coronary angiography with a view to revascularisation? Why this is important Revascularisation has traditionally been offered to people with stable angina who have evidence of reversible ischaemia on non-invasive functional testing. Recent trials in people with stable angina (COURAGE, BARI-2D, MASS II) have not shown survival benefit from revascularisation compared with drug treatment. In the nuclear substudy of COURAGE (n = 314), PCI was shown to be more effective in treating ischaemia than optimal drug treatment, and in multivariate analyses reduction of ischaemia was associated with greater event-free survival. It is unclear, however, whether people on optimal drug treatment who have evidence of inducible ischaemia on non-invasive functional testing should routinely have coronary angiography and revascularisation. This question is particularly relevant for people who have responded adequately (for example Canadian Cardiovascular Class 1 or 2) to optimal drug treatment and in whom, based on symptoms alone, revascularisation is not indicated.


This question is particularly relevant for people who have responded adequately (for example Canadian Cardiovascular Class 1 or 2) to optimal drug treatment and in whom, based on symptoms alone, revascularisation is not indicated. To answer this question we recommend a randomised trial of interventional management versus continued drug treatment in people with stable angina and myocardial ischaemia on non-invasive functional testing, with all-cause mortality and cardiovascular mortality as the primary endpoints. 3 Early revascularisation strategy for people with angina and multivessel disease In people with stable angina and multivessel disease (including left main stem disease) whose symptoms are controlled with optimal drug treatment, would an initial treatment strategy of revascularisation be clinically and cost effective compared with continued drug treatment? Why this is important Research is needed to determine whether early investigation and revascularisation can improve longer term survival. People with stable angina may be disadvantaged if they do not have tests to identify whether they have a higher risk profile for early cardiac death, which could be reduced by revascularisation. This disadvantage could be magnified when people who are deemed to fall into very high risk groups (for example, left main stem stenosis > 50% in the MASS II trial) are excluded from randomised trials, resulting in the benefits of revascularisation being underestimated. We propose a randomised trial comparing an initial strategy of revascularisation (CABG or PCI) with an initial strategy of continued drug treatment in people with multivessel disease (including left main stem disease) in whom revascularisation is not needed for symptom relief. The trial should use drug-eluting stents and wider inclusion criteria than BARI-2D and COURAGE. 4 Cardiac rehabilitation Is an 8-week, comprehensive, multidisciplinary, cardiac rehabilitation service more clinically and cost effective for managing stable angina than current clinical practice?


4 Cardiac rehabilitation Is an 8-week, comprehensive, multidisciplinary, cardiac rehabilitation service more clinically and cost effective for managing stable angina than current clinical practice? Why this is important Cardiac rehabilitation programmes are an established treatment strategy for certain heart conditions, such as for people who have had a heart attack. However, there is no evidence to suggest that cardiac rehabilitation is clinically or cost effective for managing stable angina. Research to date has looked at short-term outcomes, such as a change in diet or exercise levels, but the effect on morbidity and mortality has not been studied. A randomised controlled trial is required to compare comprehensive cardiac rehabilitation with standard care in people with stable angina, with measures of angina severity (exercise capacity, angina frequency, use of a short-acting nitrate), and long-term morbidity and mortality as endpoints. 5 Patient self-management plans What is the clinical and cost effectiveness of a self-management plan for people with stable angina? Why this is important Stable angina is a chronic condition. Evidence suggests that addressing people's beliefs and behaviours in relation to angina may improve quality of life, and reduce morbidity and use of resources. Self-management plans could include: educating people with stable angina about the role of psychological factors in pain and pain control; and teaching people self-management skills to modify cognitions, behaviours and affective responses in order to control chest pain. These skills may include pacing of physical activities, modifying stress using cognitive reframing and problem-solving techniques, and relaxation training or mindfulness techniques. The proposed study is a randomised controlled trial in primary care that would assess the clinical and cost effectiveness of self-management plans. This research would inform future updates of key recommendations in the guideline.


This research would inform future updates of key recommendations in the guideline. Furthermore the research would be relevant to a national priority area (National service framework for coronary heart disease [NSF CHD] chapter 4: stable angina and chapter 7: cardiac rehabilitation) as well as the Coalition White Paper 2010 (Equity and excellence: liberating the NHS) that emphasise the importance of increasing people's choice and control in managing their condition. Finding more information and committee details To find NICE guidance on related topics, including guidance in development, see the NICE webpage on acute coronary syndromes. For full details of the evidence and the guideline committee's discussions, see the full guideline. You can also find information about how the guideline was developed, including details of the committee. NICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting our guidelines into practice, see resources to help you put NICE guidance into practice. Update information August 2016: Added a footnote to recommendations 1.4.11 and 1.4.12 covering the new advice from the Medicines and Healthcare products Regulatory Agency (MHRA) about safety concerns related to ivabradine (June 2014 and December 2014) and nicorandil (January 2016). Minor changes since publication December 2012: The licensing information for nicorandil was updated. Accreditation


WRITING COMMITTEE MEMBERS* Catherine M. Otto, MD, FACC, FAHA, Co-Chair Rick A. Nishimura, MD, MACC, FAHA, Co-Chair Robert O. Bonow, MD, MS, MACC, FAHA Blase A. Carabello, MD, FACC, FAHA John P. Erwin III, MD, FACC, FAHA Federico Gentile, MD, FACC Hani Jneid, MD, FACC, FAHA Eric V. Krieger, MD, FACC Michael Mack, MD, MACC Christopher McLeod, MBCHB, PhD, FAHA Patrick T. O Gara, MD, MACC, FAHA Vera H. Rigolin, MD, FACC, FAHA Thoralf M. Sundt III, MD, FACC, FAHA Annemarie Thompson, MD Christopher Toly 2020 by the American College of Cardiology Foundation and the American Heart Association, Inc. ACC/AHA CLINICAL PRACTICE GUIDELINE 2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines Circulation https://www.ahajournals.org/journal/circ Developed in collaboration with and endorsed by the American Association for Thoracic Surgery, American Society of Echocardiography, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Anesthesiologists, and Society of Thoracic Surgeons ACC/AHA Joint Committee on Clinical Practice Guidelines Members, see page *Writing committee 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. ACC/AHA Joint Committee on Clinical Practice Guidelines Liaison. The American Heart Association requests that this document be cited as follows: Otto CM, Nishimura RA, Bonow RO, Carabello BA, Erwin JP 3rd, Gentile F, Jneid H, Krieger EV, Mack M, McLeod C, O Gara PT, Rigolin VH, Sundt TM 3rd, Thompson A, Toly C. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2021;143:e72-e227.


The American Heart Association requests that this document be cited as follows: Otto CM, Nishimura RA, Bonow RO, Carabello BA, Erwin JP 3rd, Gentile F, Jneid H, Krieger EV, Mack M, McLeod C, O Gara PT, Rigolin VH, Sundt TM 3rd, Thompson A, Toly C. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2021;143:e72-e227. doi: 10.1161/CIR.0000000000000923 Key Words: AHA Scientific Statements anticoagulation therapy aortic regurgitation aortic stenosis bicuspid aortic valve cardiac surgery guidelines infective endocarditis mitral regurgitation mitral stenosis mitral transcatheter edge-to-edge repair prosthetic valve pulmonic regurgitation pulmonic stenosis transcatheter aortic valve replacement or implantation tricuspid regurgitation tricuspid stenosis valvular heart disease CLINICAL STATEMENTS AND GUIDELINES TABLE OF CONTENTS Top 10 Take-Home Messages . . . . . . . . . . . . . . . . . . . . . . . . e74 Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e75 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e76 1.1. Methodology and Evidence Review . . . . . . . . . . . . e76 1.2. Organization of the Writing Committee . . . . . . . . e76 1.3. Document Review and Approval . . . . . . . . . . . . . . e76 1.4. Scope of the Guideline . .


. . e76 1.4. Scope of the Guideline . . . . . . . . . . . . . . . . . . . . . . e76 1.5. Class of Recommendation and Level of Evidence e77 1.6. Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e77 2. General Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e78 2.1. Evaluation of the Patient With Known or Suspected Native VHD . . . . . . . . . . . . . . . . . . . . . . . e78 2.2. Definitions of Severity of Valve Disease . . . . . . . . . e78 2.3. Diagnosis and Follow-Up e78 2.3.1. Diagnostic Testing: Initial Diagnosis 30 . . . e78 2.3.2. Diagnostic Testing: Changing Signs or Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . e80 2.3.3. Diagnostic Testing: Routine Follow-Up . . . . e80 2.3.4. Diagnostic Testing: Cardiac Catheterization . e81 2.3.5. Diagnostic Testing: Exercise Testing . . . . . . e81 2.4. Basic Principles of Medical Therapy . . . . . . . . . . . . e81 2.4.1. Secondary Prevention of Rheumatic Fever . e82 2.4.2. IE Prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . e82 2.4.3.


. . . . . . . . e82 2.4.3. Anticoagulation for AF in Patients With VHD e83 2.5. Evaluation of Surgical and Interventional Risk . . . e85 2.6. The Multidisciplinary Heart Valve Team and Heart Valve Centers . . . . . . . . . . . . . . . . . . . . . . . . . e86 2.7. Management of Patients With VHD After Valve Intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e88 2.7.1. Procedural Complications . . . . . . . . . . . . . . e89 2.7.2. Primary and Secondary Risk Factor Evaluation and Treatment . . . . . . . . . . . . . . e89 2.7.3. Persistent Symptoms After Valve Intervention . e89 2.7.4. Periodic Imaging After Valve Intervention . e89 3. Aortic Stenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e90 3.1. Stages of Valvular AS . . . . . . . . . . . . . . . . . . . . . . . . e90 3.2. Aortic Stenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e90 3.2.1. Diagnosis and Follow-Up . . . . . . . . . . . . . . . e90 3.2.2. Medical Therapy . . . . . . . . . . . . .


. . . . . . . . . . . . . . . . . . . e93 3.2.3. Timing of Intervention . . . . . . . . . . . . . . . . . e94 3.2.4. Choice of Intervention . . . . . . . . . . . . . . . . . e97 4. Aortic Regurgitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . e104 4.1. Acute Aortic Regurgitation . . . . . . . . . . . . . . . . . . e104 4.1.1. Diagnosis of AR . . . . . . . . . . . . . . . . . . . . . e104 4.1.2. Intervention . . . . . . . . . . . . . . . . . . . . . . . . . e104 4.2. Stages of Chronic AR . . . . . . . . . . . . . . . . . . . . . . . e104 4.3. Chronic AR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e106 4.3.1. Diagnosis of Chronic AR . . . . . . . . . . . . . . e106 4.3.2. Medical Therapy . . . . . . . . . . . . . . . . . . . . . e106 4.3.3. Timing of Intervention . . . . . . . . . . . . . .


. . . . . . . . . . . . e107 5. Bicuspid Aortic Valve . . . . . . . . . . . . . . . . . . . . . . . . . . . e109 5.1. BAV and Associated Aortopathy . . . . . . . . . . . . . e109 5.1.1. Diagnosis and Follow-Up of BAV . . . . . . . e109 5.1.2. Interventions for Patients With BAV . . . . . e109 6. Mitral Stenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e112 6.1. Stages of MS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e113 6.2. Rheumatic MS . . . . . . . . . . . . . . . . . . . . . . . . . . . . e113 6.2.1. Diagnosis and Follow-Up of Rheumatic MS e113 6.2.2. Medical Therapy . . . . . . . . . . . . . . . . . . . . . e115 6.2.3. Intervention . . . . . . . . . . . . . . . . . . . . . . . e116 6.3. Nonrheumatic Calcific MS . . . . . . . . . . . . . . . . . e118 7. Mitral Regurgitation . . . . . . . . . . . . . . . . . . . . . . . .


. . . . . . . . . . . . . e119 7.1. Acute MR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e119 7.1.1. Diagnosis of Acute MR . . . . . . . . . . . . . . e119 7.1.2. Medical Therapy . . . . . . . . . . . . . . . . . . . . e119 7.1.3. Intervention . . . . . . . . . . . . . . . . . . . . . . . e119 7.2. Chronic Primary MR . . . . . . . . . . . . . . . . . . . . . . e119 7.2.1. Stages of Chronic Primary MR . . . . . . . . e119 7.2.2. Diagnosis and Follow-Up of Chronic Primary MR . . . . . . . . . . . . . . . . . . . . . . . . e120 7.2.3. Medical Therapy . . . . . . . . . . . . . . . . . . . . e123 7.2.4. Intervention . . . . . . . . . . . . . . . . . . . . . . . e124 7.3. Chronic Secondary MR . . . . . . . . . . . . . . . . . . . . e126 7.3.1. Stages of Chronic Secondary MR . . . . . . e126 7.3.2. Diagnosis of Chronic Secondary MR . . . e127 7.3.3. Medical Therapy . . . . .


. e127 7.3.3. Medical Therapy . . . . . . . . . . . . . . . . . . . . e128 7.3.4. Intervention . . . . . . . . . . . . . . . . . . . . . . . e129 8. Tricuspid Valve Disease . . . . . . . . . . . . . . . . . . . . . . . . e131 8.1. Classification and Stages of TR . . . . . . . . . . . . . e131 8.2. Tricuspid Regurgitation . . . . . . . . . . . . . . . . . . . . e131 8.2.1. Diagnosis of TR . . . . . . . . . . . . . . . . . . . . e131 8.2.2. Medical Therapy . . . . . . . . . . . . . . . . . . . . e132 8.2.3. Timing of Intervention . . . . . . . . . . . . . . . e133 9. Pulmonic Valve Disease e135 10. Mixed Valve Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . e135 10.1. Diagnosis of Mixed VHD . . . . . . . . . . . . . . . . . . e135 10.2. Timing of Intervention for Mixed VHD . . . . . . . e136 10.2.1. Intervention for Mixed AS and AR e136 10.2.2. Intervention for Mixed AS and MR . . . e136 10.2.3. Intervention for Mixed MS and MR . . .


e136 10.2.3. Intervention for Mixed MS and MR . . . e137 10.2.4. Intervention for Mixed MS and AR . . . e137 10.2.5. Intervention for Mixed MS and AS . . . e137 11. Prosthetic Valves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e137 11.1. Evaluation and Selection of Prosthetic Valves . e137 11.1.1. Diagnosis and Follow-Up of Prosthetic Valves . . . . . . . . . . . . . . . . . . . . . . . . . . . e137 11.1.2. Selection of Prosthetic Valve Type: Bioprosthetic Versus Mechanical Valve . e139 11.2. Antithrombotic Therapy . . . . . . . . . . . . . . . . . . . e142 11.3. Bridging Therapy e146 11.4. Excessive Anticoagulation and Serious Bleeding With Prosthetic Valves . . . . . . . . . . . . e148 11.5. Thromboembolic Events With Prosthetic Valves . e148 11.6. Acute Mechanical Valve Thrombosis . . . . . . . . e149 11.6.1. Diagnosis of Acute Mechanical Valve Thrombosis . . . . . . . . . . . . . . . . . . . . . . e149 11.6.2. Intervention . . . . . . . . . . . . . . . . . . . . . e150 11.7. Bioprosthetic Valve Thrombosis . . . . . . . . . . . . . e150 11.7.1. Diagnosis of Bioprosthetic Valve Thrombosis . . . . . . . . . . . . . . . . . . . . . . e150 11.7.2. Medical Therapy .


. . . . . e150 11.7.2. Medical Therapy . . . . . . . . . . . . . . . . . . e150 11.8. Prosthetic Valve Stenosis . . . . . . . . . . . . . . . . . . e151 11.8.1.Diagnosis of Prosthetic Valve Stenosis . . . . e151 11.8.2. Intervention for Prosthetic Valve Stenosis . e152 11.9. Prosthetic Valve Regurgitation . . . . . . . . . . . . . . e152 11.9.1. Diagnosis of Prosthetic Valve Regurgitation e153 11.9.2. Medical Therapy . . . . . . . . . . . . . . . . . . e154 11.9.3. Intervention . . . . . . . . . . . . . . . . . . . . . . e154 CLINICAL STATEMENTS AND GUIDELINES 12. Infective Endocarditis . . . . . . . . . . . . . . . . . . . . . . . . . . e155 12.1. Classification of Endocarditis . . . . . . . . . . . . . . e155 12.2. Diagnosis of IE . . . . . . . . . . . . . . . . . . . . . . . . . . e156 12.3. Medical Therapy . . . . . . . . . . . . . . . . . . . . . . . . e160 12.4. Intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . e162 13. Pregnancy and VHD . . . . . . . . . . .


. . . . . . . . . . . . . . . . . . . . . . . . . . e165 13.1. Initial Management of Women With VHD Before and During Pregnancy . . . . . . . . . . . . . e165 13.1.1. Medical Therapy for Women With VHD Before and During Pregnancy e166 13.1.2. Intervention for Women With Native VHD Before and During Pregnancy e166 13.2. Prosthetic Valves in Pregnant Women . . . . . . . e169 13.2.1. Initial Management . . . . . . . . . . . . . . . e169 13.2.2. Anticoagulation for Pregnant Women With Mechanical Prosthetic Heart Valves . . . . . . . . . . . . . . . . . . . . . . . . . . e170 14. Surgical Considerations . . . . . . . . . . . . . . . . . . . . . . . . e174 14.1. Evaluation and Management of CAD in Patients With VHD . . . . . . . . . . . . . . . . . . . . . . . e174 14.1.1. Management of CAD in Patients Undergoing TAVI . . . . . . . . . . . . . . . . . e174 14.1.2. Management of CAD in Patients Undergoing Valve Surgery . . . . . . . . . e176 14.2. Intervention for AF in Patients With VHD . . . . e177 15. Noncardiac Surgery in Patients With VHD . . . . . . . . . e178 15.1. Diagnosis of Patients With VHD Undergoing Noncardiac Surgery . . . . . . . .


Diagnosis of Patients With VHD Undergoing Noncardiac Surgery . . . . . . . . . . . . . . . . . . . . . . e178 15.2. Management of the Symptomatic Patient . . . e179 15.3. Management of the Asymptomatic Patient . . e180 16. Evidence Gaps and Future Directions . . . . . . . . . . . . . e181 16.1. Prevention of Valve Disease: Stage A . . . . . . . e181 16.2. Medical Therapy to Treat or Prevent Disease Progression: Stage B . . . . . . . . . . . . . . . . . . . . . e182 16.3. Optimal Timing of Intervention: Stage C . . . . e182 16.4. Better Options for Intervention: Stage D e182 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e184 Appendix 1. Author Relationships With Industry and Other Entities (Relevant) . . . . . . . . . . . . . . . . . . . . . . . . . e222 Appendix 2. Reviewer Relationships With Industry and Other Entities (Comprehensive) . . . . . . . . . . . . . . . . . . . e224 TOP 10 TAKE-HOME MESSAGES 1. Disease stages in patients with valvular heart dis- ease should be classified (Stages A, B, C, and D) on the basis of symptoms, valve anatomy, the severity of valve dysfunction, and the response of the ventricle and pulmonary circulation. 2.


Disease stages in patients with valvular heart dis- ease should be classified (Stages A, B, C, and D) on the basis of symptoms, valve anatomy, the severity of valve dysfunction, and the response of the ventricle and pulmonary circulation. 2. In the evaluation of a patient with valvular heart disease, history and physical examination find- ings should be correlated with the results of noninvasive testing (ie, ECG, chest x-ray, trans- thoracic echocardiogram). If there is discordance between the physical examination and initial noninvasive testing, consider further noninva- sive (computed tomography, cardiac magnetic resonance imaging, stress testing) or invasive (transesophageal echocardiography, cardiac catheterization) testing to determine optimal treatment strategy. 3. For patients with valvular heart disease and atrial fibrillation (except for patients with rheumatic mitral stenosis or a mechanical prosthesis), the decision to use oral anticoagulation to prevent thromboembolic events, with either a vitamin K antagonist or a non vitamin K antagonist anti- coagulant, should be made in a shared decision- making process based on the CHA2 -VASc score. Patients with rheumatic mitral stenosis or a mechanical prosthesis and atrial fibrillation should receive oral anticoagulation with a vitamin K antagonist. 4. All patients with severe valvular heart disease being considered for valve intervention should be evaluated by a multidisciplinary team, with either referral to or consultation with a Primary or Comprehensive Valve Center. 5. Treatment of severe aortic stenosis with either a transcatheter or surgical valve prosthesis should be based primarily on symptoms or reduced ven- tricular systolic function. Earlier intervention may be considered if indicated by results of exercise testing, biomarkers, rapid progression, or the presence of very severe stenosis. 6. Indications for transcatheter aortic valve implan- tation are expanding as a result of multiple randomized trials of transcatheter aortic valve implantation versus surgical aortic valve replace- ment.


Indications for transcatheter aortic valve implan- tation are expanding as a result of multiple randomized trials of transcatheter aortic valve implantation versus surgical aortic valve replace- ment. The choice of type of intervention for a patient with severe aortic stenosis should be a shared decision-making process that considers the lifetime risks and benefits associated with type of valve (mechanical versus bioprosthetic) and type of approach (transcatheter versus surgical). 7. Indications for intervention for valvular regurgi- tation are relief of symptoms and prevention of the irreversible long-term consequences of left ventricular volume overload. Thresholds for inter- vention now are lower than they were previously because of more durable treatment options and lower procedural risks. 8. A mitral transcatheter edge-to-edge repair is of benefit to patients with severely symptomatic primary mitral regurgitation who are at high or prohibitive risk for surgery, as well as to a select subset of patients with secondary mitral regurgi- tation who remain severely symptomatic despite guideline-directed management and therapy for heart failure. 9. Patients presenting with severe symptomatic iso- lated tricuspid regurgitation, commonly associ- ated with device leads and atrial fibrillation, may benefit from surgical intervention to reduce symp- toms and recurrent hospitalizations if done before CLINICAL STATEMENTS AND GUIDELINES the onset of severe right ventricular dysfunction or end-organ damage to the liver and kidney. 10. Bioprosthetic valve dysfunction may occur because of either degeneration of the valve leaflets or valve thrombosis. Catheter-based treatment for prosthetic valve dysfunction is reasonable in selected patients for bioprosthetic leaflet degeneration or paravalvular leak in the absence of active infection. PREAMBLE Since 1980, the American College of Cardiology (ACC) and American Heart Association (AHA) have translated sci- entific evidence into clinical practice guidelines with recom- mendations to improve cardiovascular health.


PREAMBLE Since 1980, the American College of Cardiology (ACC) and American Heart Association (AHA) have translated sci- entific evidence into clinical practice guidelines with recom- mendations to improve cardiovascular health. These guide- lines, which are based on systematic methods to evaluate and classify evidence, provide a foundation for the delivery of quality cardiovascular care. The ACC and AHA sponsor the development and publication of clinical practice guide- lines without commercial support, and members volunteer their time to the writing and review efforts. Guidelines are official policy of the ACC and AHA. For some guidelines, the ACC and AHA partner with other organizations. 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 in- tent 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, cir- cumstances, 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 Joint Committee on Clinical Practice Guidelines (Joint Committee) continuously reviews, up- dates, and modifies guideline methodology on the ba- sis of published standards from organizations, including the Institute of Medicine,1,2 and on the basis of internal reevaluation.


Methodology and Modernization The ACC/AHA Joint Committee on Clinical Practice Guidelines (Joint Committee) continuously reviews, up- dates, and modifies guideline methodology on the ba- sis of published standards from organizations, including the Institute of Medicine,1,2 and on the basis of internal reevaluation. Similarly, presentation and delivery of guidelines are reevaluated and modified in response to evolving technologies and other factors to optimally fa- cilitate dissemination of information to healthcare pro- fessionals at the point of care. Numerous modifications to the guidelines have been implemented to make them shorter and enhance user- friendliness. Guidelines are written and presented in a modular knowledge chunk format, in which each chunk includes a table of recommendations, a brief synopsis, recommendation-specific supportive text and, when appropriate, flow diagrams or additional tables. Hyperlinked references are provided for each modular knowledge chunk to facilitate quick access and review. Word limit targets and a web supplement for useful but noncritical tables and figures are 2 recent modifications. 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 will be reviewed on an ongoing ba- sis by the writing committee and staff. Going forward, targeted sections or knowledge chunks will be revised dynamically after publication and timely peer review of potentially practice-changing science. The previous designations of full revision and focused update will be phased out.


The previous designations of full revision and focused update will be phased out. For additional information and poli- cies on guideline development, readers may consult the ACC/AHA guideline methodology manual4 and other Selection of Writing Committee Members The Joint Committee strives to ensure that the guide- line writing committee members have requisite content expertise and are representative of the broader cardio- vascular community. Experts are selected across a spec- trum of backgrounds, representing different geographic regions, sexes, races, ethnicities, intellectual perspectives or biases, and clinical practice settings. Organizations and professional societies with related interests and expertise are invited 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 re- lationships with industry and other entities (RWI) can be found at https://www.acc.org/guidelines/about- guidelines-and-clinical-documents/relationships-with- industry-policy. Appendix 1 of the guideline lists writing committee members relevant RWI; for the purposes of CLINICAL STATEMENTS AND GUIDELINES full transparency, their comprehensive disclosure infor- mation is available online (https://www.ahajournals.org/ hensive disclosure information for the Joint Commit- tee is also available at https://www.acc.org/guidelines/ about-guidelines-and-clinical-documents/guidelines- and-documents-task-forces. Evidence Review and Evidence Review Committees In developing recommendations, the writing com- mittee uses evidence-based methodologies that are based on all available data.4 5 Literature searches fo- cus on randomized controlled trials (RCTs) but also include registries, nonrandomized comparative and descriptive studies, case series, cohort studies, sys- tematic reviews, and expert opinion. Only key refer- ences are cited. An independent evidence review committee is commissioned when there are one or more questions deemed of utmost clinical importance that merit for- mal systematic review to determine which patients are most likely to benefit from a drug, device, or treatment strategy, and to what degree.


An independent evidence review committee is commissioned when there are one or more questions deemed of utmost clinical importance that merit for- mal systematic review to determine which patients are most likely to benefit from a drug, device, or treatment strategy, and to what degree. Criteria for commissioning an evidence review committee and formal systematic review include absence of a current authoritative systematic review, feasibility of defining the benefit and risk in a time frame consistent with the writing of a guideline, relevance to a substantial number of patients, and likelihood that the findings can be translated into actionable recommendations. Evidence review committee members may include methodologists, epidemiologists, clinicians, and bio- statisticians. Recommendations developed by the writing committee on the basis of the systematic re- view are marked SR . Guideline-Directed Management and Therapy The term guideline-directed management and therapy (GDMT) encompasses clinical evaluation, diagnos- tic testing, and both pharmacological and procedural treatments. For these and all recommended drug treat- ment regimens, the reader should confirm dosage with product insert material and evaluate for contraindica- tions and interactions. Recommendations are limited to drugs, devices, and treatments approved for clinical use in the United States. Patrick T. O Gara, MD, MACC, FAHA Chair, ACC/AHA Joint Committee on Clinical Practice Guidelines 1.1. Methodology and Evidence Review The recommendations listed in this document are, whenever possible, evidence based. An extensive review was conducted on literature published through March 1, 2020. Searches were extended to studies, reviews, and other evidence involving human subjects that were published in English and indexed in PubMed, EMBASE, Cochrane, Agency for Healthcare Research and Quality Reports, and other selected databases relevant to this guideline.


Searches were extended to studies, reviews, and other evidence involving human subjects that were published in English and indexed in PubMed, EMBASE, Cochrane, Agency for Healthcare Research and Quality Reports, and other selected databases relevant to this guideline. Key search words included but were not limit- ed to the following: valvular heart disease, aortic steno- sis, aortic regurgitation, bicuspid aortic valve, mitral ste- nosis, mitral regurgitation, tricuspid stenosis, tricuspid regurgitation, pulmonic stenosis, pulmonic regurgita- tion, prosthetic valves, anticoagulation therapy, infective endocarditis, cardiac surgery, transcatheter aortic valve replacement or implantation, and percutaneous mitra- clip. Additionally, the committee reviewed documents related to the subject matter previously published by the ACC and AHA. The references selected and published in this document are representative and not all-inclusive. 1.2. Organization of the Writing Committee The writing committee was composed of clinicians, which included cardiologists, interventionalists, sur- geons, anesthesiologists, and a patient representative. Members were required to disclose all RWI relevant to the data under consideration. 1.3. Document Review and Approval This document was reviewed by 2 official reviewers each nominated by the ACC and the AHA, as well as content reviewers nominated by the ACC and AHA. Reviewers RWI information was distributed to the writing commit- tee and is published in this document (Appendix 2). 1.4. Scope of the Guideline The focus of this guideline is the diagnosis and man- agement of adult patients with valvular heart disease (VHD). A full revision of the original 1998 VHD guide- line was made in 2006, and an update was made in Another full revision was made in 2014,2 with an update in 2017.3 There was an additional statement of clarification specifically for surgery for aortic dilation in patients with bicuspid aortic valves (BAV) in 2016.4 The present guideline will replace the 2014 guideline and 2017 focused update.


A full revision of the original 1998 VHD guide- line was made in 2006, and an update was made in Another full revision was made in 2014,2 with an update in 2017.3 There was an additional statement of clarification specifically for surgery for aortic dilation in patients with bicuspid aortic valves (BAV) in 2016.4 The present guideline will replace the 2014 guideline and 2017 focused update. Some recommendations from the earlier VHD guidelines have been updated as war- ranted by new evidence or a better understanding of CLINICAL STATEMENTS AND GUIDELINES earlier evidence, whereas others that were inaccurate, irrelevant, or overlapping were deleted or modified. Throughout, our goal was to provide the clinician with concise, evidence-based, contemporary recommenda- tions and the supporting documentation to encourage their use. Where applicable, sections were divided into subsections of 1) diagnosis and follow-up, 2) medical therapy, and 3) intervention. The purpose of these sub- sections is to categorize the Class of Recommendation according to the clinical decision-making pathways that caregivers use in the management of patients with VHD. The document recommends a combination of life- style modifications and medications that constitute components of GDMT. For both GDMT and other rec- ommended drug treatment regimens, the reader is advised to confirm dosages with product insert mate- rial and to carefully evaluate for contraindications and drug drug interactions. Table 1 is a list of associated guidelines that may be of interest to the reader. 1.5. 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 2).1 Table 1.


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 2).1 Table 1. Associated Guidelines and Related References Title Organization Publication Year (Reference) Recommendations for Evaluation of the Severity of Native Valvular Regurgitation With Two-Dimensional and Doppler Echocardiography European Association of Echocardiography Recommendations for the Assessment of Valvular Regurgitation, Part 2: Mitral and Tricuspid Regurgitation (Native Valve Disease) Guidelines for the Management of Patients With Atrial Fibrillation ACC/AHA/ESC 2006, 2008, 20197 9 Guidelines for the Management of Adults With Congenital Heart Disease ACC/AHA 201810 Echocardiographic Assessment of Valve Stenosis: EAE/ASE Recommendations for Clinical Practice EAE/ASE 200911 Recommendations on the Echocardiographic Assessment of Aortic Valve Stenosis: A Focused Update from the European Association of Cardiovascular Imaging and the American Society of Echocardiography Guidelines for the Evaluation of Valvular Regurgitation After Percutaneous Valve Repair or Replacement: A Report from the American Society of Echocardiography Recommendations for Evaluation of Prosthetic Valves With Echocardiography and Doppler Ultrasound ASE 200914 Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy ACCF/AHA 201115 Guidelines on the Management of Cardiovascular Diseases During Pregnancy ESC 2011, 201817, 18 Antithrombotic and Thrombolytic Therapy for Valvular Disease: Antithrombotic Therapy and Prevention of Thrombosis ACCP 201219 Guidelines on the Management of Valvular Heart Disease ESC/EACTS 201220 Guideline for the Management of Heart Failure ACCF/AHA 201722 ACC indicates American College of Cardiology; ACCF, American College of Cardiology Foundation; ACCP, American College of Chest Physicians; AHA, American Heart Association; ASE, American Society of Echocardiography; EACI, European Association of Cardiovascular Imaging; EACTS, European Association of Cardio Thoracic Surgery; EAE, European Association of Echocardiography; and ESC, European Society of Cardiology.


Associated Guidelines and Related References Title Organization Publication Year (Reference) Recommendations for Evaluation of the Severity of Native Valvular Regurgitation With Two-Dimensional and Doppler Echocardiography European Association of Echocardiography Recommendations for the Assessment of Valvular Regurgitation, Part 2: Mitral and Tricuspid Regurgitation (Native Valve Disease) Guidelines for the Management of Patients With Atrial Fibrillation ACC/AHA/ESC 2006, 2008, 20197 9 Guidelines for the Management of Adults With Congenital Heart Disease ACC/AHA 201810 Echocardiographic Assessment of Valve Stenosis: EAE/ASE Recommendations for Clinical Practice EAE/ASE 200911 Recommendations on the Echocardiographic Assessment of Aortic Valve Stenosis: A Focused Update from the European Association of Cardiovascular Imaging and the American Society of Echocardiography Guidelines for the Evaluation of Valvular Regurgitation After Percutaneous Valve Repair or Replacement: A Report from the American Society of Echocardiography Recommendations for Evaluation of Prosthetic Valves With Echocardiography and Doppler Ultrasound ASE 200914 Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy ACCF/AHA 201115 Guidelines on the Management of Cardiovascular Diseases During Pregnancy ESC 2011, 201817, 18 Antithrombotic and Thrombolytic Therapy for Valvular Disease: Antithrombotic Therapy and Prevention of Thrombosis ACCP 201219 Guidelines on the Management of Valvular Heart Disease ESC/EACTS 201220 Guideline for the Management of Heart Failure ACCF/AHA 201722 ACC indicates American College of Cardiology; ACCF, American College of Cardiology Foundation; ACCP, American College of Chest Physicians; AHA, American Heart Association; ASE, American Society of Echocardiography; EACI, European Association of Cardiovascular Imaging; EACTS, European Association of Cardio Thoracic Surgery; EAE, European Association of Echocardiography; and ESC, European Society of Cardiology. Abbreviation Meaning/Phrase ACE angiotensin-converting enzyme AF atrial fibrillation ARB angiotensin receptor blocker aPTT activated partial thromboplastin time AR aortic regurgitation AS aortic stenosis AVR aortic valve replacement BAV bicuspid aortic valve BNP B-type natriuretic peptide CABG coronary artery bypass graft surgery CAD coronary artery disease CMR cardiac magnetic resonance COR Class of Recommendation CT computed tomography ECG electrocardiogram GDMT guideline-directed management and therapy HF heart failure IE infective endocarditis INR international normalized ratio LA left atrium (left atrial) LMWH low-molecular-weight heparin CLINICAL STATEMENTS AND GUIDELINES 2.


Abbreviation Meaning/Phrase ACE angiotensin-converting enzyme AF atrial fibrillation ARB angiotensin receptor blocker aPTT activated partial thromboplastin time AR aortic regurgitation AS aortic stenosis AVR aortic valve replacement BAV bicuspid aortic valve BNP B-type natriuretic peptide CABG coronary artery bypass graft surgery CAD coronary artery disease CMR cardiac magnetic resonance COR Class of Recommendation CT computed tomography ECG electrocardiogram GDMT guideline-directed management and therapy HF heart failure IE infective endocarditis INR international normalized ratio LA left atrium (left atrial) LMWH low-molecular-weight heparin CLINICAL STATEMENTS AND GUIDELINES 2. GENERAL PRINCIPLES 2.1. Evaluation of the Patient With Known or Suspected Native VHD Patients with VHD may present with a heart murmur, symptoms, or incidental findings of valvular abnormali- ties on noninvasive testing. Irrespective of the presenta- tion, all patients with known or suspected VHD should undergo an initial meticulous history and physical ex- amination. A detailed physical examination should be performed to diagnose and assess the severity of valve lesions. An electrocardiogram (ECG) to confirm heart rhythm and a chest x-ray to assess the presence or ab- sence of pulmonary congestion or other lung pathology may be helpful in the initial assessment of patients with known or suspected VHD. A comprehensive transtho- racic echocardiogram (TTE) with 2-dimensional (2D) im- aging and Doppler interrogation should be performed for diagnosis and evaluation of known or suspected VHD. The TTE also provides additional information, such as the effect of the valve lesion on the cardiac chambers and great vessels, as well as an assessment of other valve lesions. To determine the optimal treat- ment for a patient with VHD, ancillary testing may be required, such as transesophageal echocardiography (TEE), computed tomography (CT), cardiac magnetic resonance (CMR) imaging, stress testing, Holter moni- toring, diagnostic hemodynamic cardiac catheteriza- tion, or positron emission tomography (PET) combined with CT imaging.