54. van der Meer FJ, Rosendaal FR, Vandenbroucke JP, Bri t E. Bleeding complications in oral anticoagulant therapy. An anal- ysis of risk factors. Arch Intern Med. 1993;153(13):1557-1562. 55. Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B. Placebo-controlled, randomised trial of warfa- rin and aspirin for prevention of thromboembolic complica- tions in chronic atrial brillation. The Copenhagen AFASAK study. Lancet. 1989;1(8631):175-179. 56. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial brillation. N Engl J Med. 1990;323(22):1505-1511. 57. Connolly SJ, Laupacis A, Gent M, Roberts RS, Cairns JA, Joyner C. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol. 1991;18(2):349-355. 58. Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation. 1991;84(2):527-539. 59. Ezekowitz MD, Bridgers SL, James KE, et al; Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. Warfarin in the prevention of stroke associ- ated with nonrheumatic atrial brillation. N Engl J Med. 1992;327(20):1406-1412. on Practice Guidelines; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association; Heart Rhythm Society. ACC/AHA/ ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114(7):e257-e354. 30. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classi cation schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285(22):2864-2870. 31. Albers GW, Dalen JE, Laupacis A, Manning WJ, Petersen P, Singer DE. Antithrombotic therapy in atrial brillation.


Albers GW, Dalen JE, Laupacis A, Manning WJ, Petersen P, Singer DE. Antithrombotic therapy in atrial brillation. Chest. 2001;119( suppl 1):194S-206S. 32. Wang TJ, Massaro JM, Levy D, et al. A risk score for pre- dicting stroke or death in individuals with new-onset atrial brillation in the community: the Framingham Heart Study. JAMA. 2003;290(8):1049-1056. 33. van Walraven C, Hart RG, Wells GA, et al. A clinical pre- diction rule to identify patients with atrial brillation and a low risk for stroke while taking aspirin. Arch Intern Med. 2003;163(8):936-943. 34. Singer DE, Albers GW, Dalen JE, Go AS, Halperin JL, Manning WJ. Antithrombotic therapy in atrial brillation: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(suppl 3):429S-456S. 35. Lip GY, Lane D, Van Walraven C, Hart RG. Additive role of plasma von Willebrand factor levels to clinical factors for risk strati cation of patients with atrial brillation. Stroke. 2006;37(9):2294-2300. 36. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Re ning clinical risk strati cation for predicting stroke and thromboembolism in atrial brillation using a novel risk factor-based approach: the euro heart survey on atrial bril- lation. Chest. 2010;137(2):263-272. 37. Gage BF, van Walraven C, Pearce L, et al. Selecting patients with atrial brillation for anticoagulation: stroke risk strati cation in patients taking aspirin. Circulation. 2004;110(16):2287-2292. 38. Baruch L, Gage BF, Horrow J, et al. Can patients at ele- vated risk of stroke treated with anticoagulants be further risk strati ed? Stroke. 2007;38(9):2459-2463. 39. Fang MC, Go AS, Chang Y, Borowsky L, Pomernacki NK, Singer DE; ATRIA Study Group. Comparison of risk strat- i cation schemes to predict thromboembolism in people with nonvalvular atrial brillation. J Am Coll Cardiol. 2008;51(8):810-815. 40.


Comparison of risk strat- i cation schemes to predict thromboembolism in people with nonvalvular atrial brillation. J Am Coll Cardiol. 2008;51(8):810-815. 40. Poli D, Lip GY, Antonucci E, Grifoni E, Lane D. Stroke risk strati cation in a real-world elderly anticoagulated atrial brillation population. J Cardiovasc Electrophysiol. 2010;22(1):25-30. 41. Ruiz Ortiz M, Romo E, Mesa D, et al. Oral anticoagulation in nonvalvular atrial brillation in clinical practice: impact of CHADS(2) score on outcome. Cardiology. 2010;115(3): 200-204. 42. Lip GY, Frison L, Halperin JL, Lane DA. Identifying patients at high risk for stroke despite anticoagulation: a comparison of contemporary stroke risk strati cation schemes in an anticoagulated atrial brillation cohort. Stroke. 2010;41(12):2731-2738. 43. Van Staa TP, Setakis E, Di Tanna GL, Lane DA, Lip GY. A comparison of risk strati cation schemes for stroke in e572S Antithrombotic Therapy for Atrial Fibrillation sus warfarin in the secondary prevention of major vascu- lar events in nonrheumatic atrial brillation. Stroke. 1997; 28(5):1015-1021. 75. Warfarin versus aspirin for prevention of thromboem- bolism in atrial brillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet. 1994;343(8899):687-691. 76. Adjusted-dose warfarin versus low-intensity, xed-dose warfarin plus aspirin for high-risk patients with atrial bril- lation: Stroke Prevention in Atrial Fibrillation III ran- domised clinical trial. Lancet. 1996;348(9028):633-638. 77. Rash A, Downes T, Portner R, Yeo WW, Morgan N, Channer KS. A randomised controlled trial of warfarin ver- sus aspirin for stroke prevention in octogenarians with atrial brillation (WASPO). Age Ageing. 2007;36(2):151-156. 78. Anand SS, Yusuf S. Oral anticoagulants in patients with coro- nary artery disease. J Am Coll Cardiol. 2003;41(4)(suppl S): 62S-69S. 79. Chimowitz MI, Lynn MJ, Howlett-Smith H, et al; Warfarin- Aspirin Symptomatic Intracranial Disease Trial Investigators. Comparison of warfarin and aspirin for symptomatic intra- cranial arterial stenosis. N Engl J Med. 2005;352(13):1305-1316. 80.


Comparison of warfarin and aspirin for symptomatic intra- cranial arterial stenosis. N Engl J Med. 2005;352(13):1305-1316. 80. Connolly S, Pogue J, Hart R, et al; ACTIVE Writing Group of the ACTIVE Investigators. Clopidogrel plus aspirin ver- sus oral anticoagulation for atrial brillation in the Atrial brillation Clopidogrel Trial with Irbesartan for preven- tion of Vascular Events (ACTIVE W): a randomised con- trolled trial. Lancet. 2006;367(9526):1903-1912. 81. Connolly SJ, Pogue J, Hart RG, et al; ACTIVE Investigators. Effect of clopidogrel added to aspirin in patients with atrial brillation. N Engl J Med. 2009;360(20):2066-2078. 82. Olsson SB; Executive Steering Committee of the SPORTIF III Investigators. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial brillation (SPORTIF III): randomised controlled trial. Lancet. 2003; 362(9397):1691-1698. 83. Albers GW, Diener HC, Frison L, et al; SPORTIF Execu- tive Steering Committee for the SPORTIF V Investigators. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial brillation: a randomized trial. JAMA. 2005;293(6):690-698. 84. Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial brillation. N Engl J Med. 2009;361(12):1139-1151. 85. Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial brillation. N Engl J Med. 2011;365(10):883-891. 86. Connolly SJ, Eikelboom J, Joyner C, et al; AVERROES Steering Committee and Investigators. Apixaban in patients with atrial brillation. N Engl J Med. 2011;364(9):806-817. 87. Granger CB, Alexander JH, McMurray JJ, et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial brillation. N Engl J Med. 2011;365(11): 981-992. 88. Roskell NS, Lip GY, Noack H, Clemens A, Plumb JM. Treatments for stroke prevention in atrial brillation: a network meta-analysis and indirect comparisons versus dab- igatran etexilate. Thromb Haemost. 2010;104(6):1106-1115. 89.


Treatments for stroke prevention in atrial brillation: a network meta-analysis and indirect comparisons versus dab- igatran etexilate. Thromb Haemost. 2010;104(6):1106-1115. 89. Label approved on 03/04/2011 for Pradaxa, NDA no. 022512. In: United States Food and Drug Administration; 2010. 90. van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate a novel, reversible, oral direct thrombin inhibitor: interpre- tation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103(6):1116-1127. 91. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: antithrombotic 60. EAFT (European Atrial Fibrillation Trial) Study Group. Secondary prevention in non-rheumatic atrial brillation after transient ischaemic attack or minor stroke. Lancet. 1993;342(8882):1255-1262. 61. van Walraven C, Hart RG, Singer DE, et al. Oral anticoagu- lants vs aspirin in nonvalvular atrial brillation: an individual patient meta-analysis. JAMA. 2002;288(19):2441-2448 62. Benavente O, Hart R, Koudstaal P, Laupacis A, McBride R. Antiplatelet therapy for preventing stroke in patients with atrial brillation and no previous history of stroke or transient ischemic attacks. In: Warlow C, Van Gijn J, Sandercock P, eds. Stroke Module of the Cochrane Database of Systematic Reviews. Oxford, England: The Cochrane Collaboration; 1999. 63. Posada IS, Barriales V; LASAF Pilot Study Group. Alternate- day dosing of aspirin in atrial brillation. Am Heart J. 1999; 138(1 pt 1):137-143. 64. Sato H, Ishikawa K, Kitabatake A, et al; Japan Atrial Fibril- lation Stroke Trial Group. Low-dose aspirin for preven- tion of stroke in low-risk patients with atrial brillation: Japan Atrial Fibrillation Stroke Trial. Stroke. 2006;37(2): 447-451. 65. Diener HC, Lowenthal A. Antiplatelet therapy to prevent stroke: risk of brain hemorrhage and ef cacy in atrial bril- lation. J Neurol Sci. 1997;153(1):112. 66.


Diener HC, Lowenthal A. Antiplatelet therapy to prevent stroke: risk of brain hemorrhage and ef cacy in atrial bril- lation. J Neurol Sci. 1997;153(1):112. 66. Edvardsson N, Juul-M ller S, Omblus R, Pehrsson K. Effects of low-dose warfarin and aspirin versus no treat- ment on stroke in a medium-risk patient population with atrial brillation. J Intern Med. 2003;254(1):95-101. 67. Baigent C, Blackwell L, Collins R, et al; Antithrombotic Trialists (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta- analysis of individual participant data from randomised trials. Lancet. 2009;373(9678):1849-1860. 68. Antithrombotic Trialists Collaboration; Baigent C, Blackwell L, Collins R, et al. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myo- cardial infarction, and stroke in high risk patients. BMJ. 2002;324(7329):71-86. 69. Vemmos KN, Tsivgoulis G, Spengos K, et al. Primary pre- vention of arterial thromboembolism in the oldest old with atrial brillation a randomized pilot trial comparing adjusted-dose and xed low-dose coumadin with aspirin. Eur J Intern Med. 2006;17(1):48-52. 70. Gull v AL, Koefoed BG, Petersen P, et al. Fixed minidose warfarin and aspirin alone and in combination vs adjusted- dose warfarin for stroke prevention in atrial brillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anti- coagulation Study. Arch Intern Med. 1998;158(14):1513-1521. 71. Mant J, Hobbs FD, Fletcher K, et al; BAFTA Investigators; Midland Research Practices Network (MidReC). Warfarin versus aspirin for stroke prevention in an elderly community population with atrial brillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a ran- domised controlled trial. Lancet. 2007;370(9586):493-503. 72. P rez-G mez F, Alegr a E, Berj n J, et al; NASPEAF Investigators. Comparative effects of antiplatelet, antico- agulant, or combined therapy in patients with valvular and nonvalvular atrial brillation: a randomized multicenter study. J Am Coll Cardiol. 2004;44(8):1557-1566. 73.


Comparative effects of antiplatelet, antico- agulant, or combined therapy in patients with valvular and nonvalvular atrial brillation: a randomized multicenter study. J Am Coll Cardiol. 2004;44(8):1557-1566. 73. Hellemons BS, Langenberg M, Lodder J, et al. Primary prevention of arterial thromboembolism in non-rheumatic atrial brillation in primary care: randomised controlled trial comparing two intensities of coumarin with aspirin. BMJ. 1999;319(7215):958-964. 74. Morocutti C, Amabile G, Fattapposta F, et al; SIFA (Studio Italiano Fibrillazione Atriale) Investigators. Indobufen ver- www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e573S thrombin inhibitor in atrial brillation (SPORTIF) trials. Am Heart J. 2006;152(5):967-973. 105. Clinical review for Pradaxa, NDA 22-512. In: United States Food and Drug Administration; 2010:96. 106. Hansen ML, S rensen R, Clausen MT, et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial brillation. Arch Intern Med. 2010;170(16):1433-1441. 107. Dentali F, Douketis JD, Lim W, Crowther M. Combined aspirin-oral anticoagulant therapy compared with oral anti- coagulant therapy alone among patients at risk for cardio- vascular disease: a meta-analysis of randomized trials. Arch Intern Med. 2007;167(2):117-124. 108. Vandvik PO, Lincoff AM, Gore JM, et al. Primary and sec- ondary prevention of cardiovascular disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical prac- tice guidelines. Chest. 2012;141(2)(suppl):e637S-e668S. 109. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predic- tors, and outcome of thrombosis after successful implanta- tion of drug-eluting stents. JAMA. 2005;293(17):2126-2130. 110. Serruys PW, Strauss BH, Beatt KJ, et al. Angiographic fol- low-up after placement of a self-expanding coronary-artery stent. N Engl J Med. 1991;324(1):13-17. 111. Roubin GS, Cannon AD, Agrawal SK, et al. Intracoronary stenting for acute and threatened closure complicating per- cutaneous transluminal coronary angioplasty. Circulation. 1992;85(3):916-927. 112. Foley JB, Brown RI, Penn IM.


Intracoronary stenting for acute and threatened closure complicating per- cutaneous transluminal coronary angioplasty. Circulation. 1992;85(3):916-927. 112. Foley JB, Brown RI, Penn IM. Thrombosis and restenosis after stenting in failed angioplasty: comparison with elective stenting. Am Heart J. 1994;128(1):12-20. 113. Cook S, Windecker S. Early stent thrombosis: past, present, and future. Circulation. 2009;119(5):657-659. 114. Cosmi B, Rubboli A, Castelvetri C, Milandri M. Ticlopidine versus oral anticoagulation for coronary stenting. Cochrane Database Syst Rev. 2001;(4):CD002133. 115. Lip GY, Huber K, Andreotti F, et al; European Society of Cardiology Working Group on Thrombosis. Management of antithrombotic therapy in atrial brillation patients pre- senting with acute coronary syndrome and/or undergoing percutaneous coronary intervention/ stenting published cor- rection in Thromb Haemost. 2010;104(3):653. Dosage error in article text]. Thromb Haemost. 2010;103(1):13-28. 116. Faxon DP, Eikelboom JW, Berger PB, Holmes DR, Bhatt DL, Moliterno DJ, Becker RC, Angiolillo DJ. Consensus docu- ment: antithrombotic therapy in patients with atrial brill- ation undergoing coronary stenting: a North-American perspective. Thromb Haemost. 2011;106(4):572-584. 117. Rossini R, Musumeci G, Lettieri C, et al. Long-term out- comes in patients undergoing coronary stenting on dual oral antiplatelet treatment requiring oral anticoagulant therapy. Am J Cardiol. 2008;102(12):1618-1623. 118. Sarafoff N, Ndrepepa G, Mehilli J, et al. Aspirin and clopid- ogrel with or without phenprocoumon after drug eluting coronary stent placement in patients on chronic oral antico- agulation. J Intern Med. 2008;264(5):472-480. 119. Sambola A, Ferreira-Gonz lez I, Angel J, et al. Therapeutic strat- egies after coronary stenting in chronically anticoagulated patients: the MUSICA study. Heart. 2009;95(18):1483-1488. 120. Gao F, Zhou YJ, Wang ZJ, et al. Comparison of different antithrombotic regimens for patients with atrial brilla- tion undergoing drug-eluting stent implantation. Circ J. 2010;74(4):701-708. 121.


Comparison of different antithrombotic regimens for patients with atrial brilla- tion undergoing drug-eluting stent implantation. Circ J. 2010;74(4):701-708. 121. Rothberg MB, Celestin C, Fiore LD, Lawler E, Cook JR. Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and bene t. Ann Intern Med. 2005;143(4):241-250. therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical prac- tice guidelines. Chest. 2012;141(2)(suppl):e152S-e184S. 92. Bloom eld HE, Krause A, Greer N, et al. Meta-analysis: effect of patient self-testing and self-management of long- term anticoagulation on major clinical outcomes. Ann Intern Med. 2011;154(7):472-482. 93. Freeman JV, Zhu RP, Owens DK, et al. Cost-effectiveness of dabigatran compared with warfarin for stroke preven- tion in atrial brillation. Ann Intern Med. 2011;154(1):1-11. 94. Hughes M, Lip GY; Guideline Development Group for the NICE national clinical guideline for management of atrial brillation in primary and secondary care. Risk fac- tors for anticoagulation-related bleeding complications in patients with atrial brillation: a systematic review. QJM. 2007;100(10):599-607. 95. Beyth RJ, Quinn LM, Landefeld CS. Prospective evalua- tion of an index for predicting the risk of major bleeding in outpatients treated with warfarin. Am J Med. 1998;105(2): 91-99. 96. Landefeld CS, Goldman L. Major bleeding in outpatients treated with warfarin: incidence and prediction by fac- tors known at the start of outpatient therapy. Am J Med. 1989;87(2):144-152. 97. Shireman TI, Mahnken JD, Howard PA, Kresowik TF, Hou Q, Ellerbeck EF. Development of a contemporary bleeding risk model for elderly warfarin recipients. Chest. 2006;130(5):1390-1396. 98. Gage BF, Yan Y, Milligan PE, et al. Clinical classi cation schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J. 2006;151(3):713-719. 99. Lip GY, Frison L, Halperin JL, Lane DA.


2006;151(3):713-719. 99. Lip GY, Frison L, Halperin JL, Lane DA. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial brillation: the HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score. J Am Coll Cardiol. 2011;57(2):173-180. 100. Holmes DR, Reddy VY, Turi ZG, et al; PROTECT AF Investigators. Percutaneous closure of the left atrial append- age versus warfarin therapy for prevention of stroke in patients with atrial brillation: a randomised non-inferiority trial. Lancet. 2009;374(9689):534-542. 101. Ostermayer SH, Reisman M, Kramer PH, et al. Per- cutaneous left atrial appendage transcatheter occlusion (PLAATO system) to prevent stroke in high-risk patients with non-rheumatic atrial brillation: results from the inter- national multi-center feasibility trials. J Am Coll Cardiol. 2005;46(1):9-14. 102. Block PC, Burstein S, Casale PN, et al. Percutaneous left atrial appendage occlusion for patients in atrial bril- lation suboptimal for warfarin therapy: 5-year results of the PLAATO (Percutaneous Left Atrial Appendage Trans- catheter Occlusion) Study. JACC Cardiovasc Interv. 2009; 2(7):594-600. 103. Lechat P, Lardoux H, Mallet A, et al; FFAACS (Fluindione, Fibrillation Auriculaire, Aspirin et Contraste Spontan ) Investigators. Anticoagulant ( uindione)-aspirin combina- tion in patients with high-risk atrial brillation. A random- ized trial (Fluindione, Fibrillation Auriculaire, Aspirin et Contraste Spontan ; FFAACS). Cerebrovasc Dis. 2001;12(3): 245-252. 104. Flaker GC, Gruber M, Connolly SJ, et al; SPORTIF Investigators. Risks and bene ts of combining aspirin with anticoagulant therapy in patients with atrial brillation: an exploratory analysis of stroke prevention using an oral e574S Antithrombotic Therapy for Atrial Fibrillation of patients before nonanticoagulated cardioversion from atrial brillation and utter: an analysis of pooled trials. Am Heart J. 1995;129(1):71-75. 140. Gallagher MM, Hennessy BJ, Edvardsson N, et al.


1995;129(1):71-75. 140. Gallagher MM, Hennessy BJ, Edvardsson N, et al. Embolic complications of direct current cardioversion of atrial arrhythmias: association with low intensity of anticoagula- tion at the time of cardioversion. J Am Coll Cardiol. 2002; 40(5):926-933. 141. Berger M, Schweitzer P. Timing of thromboembolic events after electrical cardioversion of atrial brillation or utter: a retrospective analysis. Am J Cardiol. 1998;82: 1545-1547, A8. 142. Manning WJ, Leeman DE, Gotch PJ, Come PC. Pulsed Doppler evaluation of atrial mechanical function after elec- trical cardioversion of atrial brillation. J Am Coll Cardiol. 1989;13(3):617-623. 143. Nagarakanti R, Ezekowitz MD, Oldgren J, et al. Dabigatran versus warfarin in patients with atrial brillation: an anal- ysis of patients undergoing cardioversion. Circulation. 2011; 123(2):131-136. 144. Manning WJ, Silverman DI, Gordon SP, Krumholz HM, Douglas PS. Cardioversion from atrial brillation with- out prolonged anticoagulation with use of transesophageal echocardiography to exclude the presence of atrial thrombi. N Engl J Med. 1993;328(11):750-755. 145. Klein AL, Grimm RA, Murray RD, et al; Assessment of Cardioversion Using Transesophageal Echocardiography Investigators. Use of transesophageal echocardiography to guide cardioversion in patients with atrial brillation. N Engl J Med. 2001;344(19):1411-1420. 146. Hoppensteadt D, Fareed J, Klein AL, et al; Assessment of Cardioversion Using Transesophageal Echocardiography (ACUTE) II Investigators. Comparison of anticoagulant and anti-in ammatory responses using enoxaparin versus unfractionated heparin for transesophageal echocardiogra- phy-guided cardioversion of atrial brillation. Am J Cardiol. 2008;102(7):842-846. 147. Klein AL, Jasper SE, Katz WE, et al; ACUTE II Steering and Publications Committee for the ACUTE II Investigators. The use of enoxaparin compared with unfractionated heparin for short-term antithrombotic therapy in atrial bril- lation patients undergoing transoesophageal echocardiog- raphy-guided cardioversion: Assessment of Cardioversion Using Transoesophageal Echocardiography (ACUTE) II randomized multicentre study. Eur Heart J. 2006;27(23): 2858-2865.


The use of enoxaparin compared with unfractionated heparin for short-term antithrombotic therapy in atrial bril- lation patients undergoing transoesophageal echocardiog- raphy-guided cardioversion: Assessment of Cardioversion Using Transoesophageal Echocardiography (ACUTE) II randomized multicentre study. Eur Heart J. 2006;27(23): 2858-2865. 148. de Luca I, Sorino M, De Luca L, Colonna P, Del Salvatore B, Corlian L. Pre- and post-cardioversion transesopha- geal echocardiography for brief anticoagulation therapy with enoxaparin in atrial brillation patients: a prospective study with a 1-year follow-up. Int J Cardiol. 2005;102(3): 447-454. 149. Wu LA, Chandrasekaran K, Friedman PA, et al. Safety of expedited anticoagulation in patients undergoing transesoph- ageal echocardiographic-guided cardioversion. Am J Med. 2006;119(2):142-146. 150. Stellbrink C, Nixdorff U, Hofmann T, et al; ACE (Anticoagulation in Cardioversion using Enoxaparin) Study Group. Safety and ef cacy of enoxaparin compared with unfractionated heparin and oral anticoagulants for pre- vention of thromboembolic complications in cardioversion of nonvalvular atrial brillation: the Anticoagulation in Cardioversion using Enoxaparin (ACE) trial. Circulation. 2004;109(8):997-1003. 151. Stangier J. Clinical pharmacokinetics and pharmacody- namics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008;47(5):285-295. 122. Wallentin L, Becker RC, Budaj A, et al; PLATO Investi- gators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057. 123. Holmes DR Jr, Kereiakes DJ, Garg S, et al. Stent thrombo- sis. J Am Coll Cardiol. 2010;56(17):1357-1365. 124. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:494-502. 125. Sherman DG, Kim SG, Boop BS, et al; National Heart, Lung, and Blood Institute AFFIRM Investigators. Occur- rence and characteristics of stroke events in the Atrial Fibrillation Follow-up Investigation of Sinus Rhythm Management (AFFIRM) study. Arch Intern Med. 2005; 165(10):1185-1191. 126.


Occur- rence and characteristics of stroke events in the Atrial Fibrillation Follow-up Investigation of Sinus Rhythm Management (AFFIRM) study. Arch Intern Med. 2005; 165(10):1185-1191. 126. Krittayaphong R, Raungrattanaamporn O, Bhuripanyo K, et al. A randomized clinical trial of the ef cacy of radio- frequency catheter ablation and amiodarone in the treat- ment of symptomatic atrial brillation. J Med Assoc Thai. 2003;86(suppl 1):S8-S16. 127. Wazni OM, Marrouche NF, Martin DO, et al. Radiofre- quency ablation vs antiarrhythmic drugs as rst-line treat- ment of symptomatic atrial brillation: a randomized trial. JAMA. 2005;293(21):2634-2640. 128. Oral H, Pappone C, Chugh A, et al. Circumferential pul- monary-vein ablation for chronic atrial brillation. N Engl J Med. 2006;354(9):934-941. 129. Pappone C, Augello G, Sala S, et al. A randomized trial of circumferential pulmonary vein ablation versus antiar- rhythmic drug therapy in paroxysmal atrial brillation: the APAF Study. J Am Coll Cardiol. 2006;48(11):2340-2347. 130. Stabile G, Bertaglia E, Senatore G, et al. Catheter ablation treatment in patients with drug-refractory atrial brillation: a prospective, multi-centre, randomized, controlled study (Catheter Ablation For The Cure Of Atrial Fibrillation Study). Eur Heart J. 2006;27(2):216-221. 131. Ja s P, Cauchemez B, Macle L, et al. Catheter ablation ver- sus antiarrhythmic drugs for atrial brillation: the A4 study. Circulation. 2008;118(24):2498-2505. 132. Wilber DJ, Pappone C, Neuzil P, et al; ThermoCool AF Trial Investigators. Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial brillation: a randomized controlled trial. JAMA. 2010;303(4):333-340. 133. Omran H, Jung W, Rabahieh R, et al. Left atrial appendage function in patients with atrial utter. Heart. 1997;78(3): 250-254. 134. Seidl K, Hauer B, Schwick NG, Zellner D, Zahn R, Senges J. Risk of thromboembolic events in patients with atrial utter. Am J Cardiol. 1998;82(5):580-583. 135. Corrado G, Sgalambro A, Mantero A, et al.


1998;82(5):580-583. 135. Corrado G, Sgalambro A, Mantero A, et al. Thromboembolic risk in atrial utter. The FLASIEC (FLutter Atriale Societ Italiana di Ecogra a Cardiovascolare) multicentre study. Eur Heart J. 2001;22(12):1042-1051. 136. Schmidt H, von der Recke G, Illien S, et al. Prevalence of left atrial chamber and appendage thrombi in patients with atrial utter and its clinical signi cance. J Am Coll Cardiol. 2001;38(3):778-784. 137. Weiss R, Marcovitz P, Knight BP, et al. Acute changes in spontaneous echo contrast and atrial function after cardio- version of persistent atrial utter. Am J Cardiol. 1998; 82(9):1052-1055. 138. Bikkina M, Alpert MA, Mulekar M, Shakoor A, Massey CV, Covin FA. Prevalence of intraatrial thrombus in patients with atrial utter. Am J Cardiol. 1995;76(3):186-189. 139. Moreyra E, Finkelhor RS, Cebul RD. Limitations of transesophageal echocardiography in the risk assessment www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e575S 152. Antonielli E, Pizzuti A, P link s A, et al. Clinical value of left atrial appendage ow for prediction of long-term sinus rhythm maintenance in patients with nonvalvular atrial brillation. J Am Coll Cardiol. 2002;39(9):1443-1449. 153. Berry C, Stewart S, Payne EM, McArthur JD, McMurray JJ. Electrical cardioversion for atrial brillation: outcomes in real-life clinical practice. Int J Cardiol. 2001;81(1):29-35. 154. Arnar DO, Danielsen R. Factors predicting maintenance of sinus rhythm after direct current cardioversion of atrial brillation and utter: a reanalysis with recently acquired data. Cardiology. 1996;87(3):181-188. 155. Paraskevaidis IA, Dodouras T, Tsiapras D, Kremastinos DT. Prediction of successful cardioversion and maintenance of sinus rhythm in patients with lone atrial brillation. Chest. 2005;127(2):488-494. 156. P rez Y, Duval AM, Carville C, et al. Is left atrial append- age ow a predictor for outcome of cardioversion of nonval- vular atrial brillation? A transthoracic and transesophageal echocardiographic study. Am Heart J. 1997;134(4):745-751. 157.


A transthoracic and transesophageal echocardiographic study. Am Heart J. 1997;134(4):745-751. 157. Page RL, Wilkinson WE, Clair WK, McCarthy EA, Pritchett EL. Asymptomatic arrhythmias in patients with symptom- atic paroxysmal atrial brillation and paroxysmal supraven- tricular tachycardia. Circulation. 1994;89(1):224-227. 158. Stoddard MF, Dawkins PR, Prince CR, Ammash NM. Left atrial appendage thrombus is not uncommon in patients with acute atrial brillation and a recent embolic event: a transesophageal echocardiographic study. J Am Coll Cardiol. 1995;25(2):452-459. 159. Kleemann T, Becker T, Strauss M, Schneider S, Seidl K. Pre- valence of left atrial thrombus and dense spontaneous echo contrast in patients with short-term atrial brillation ,48 hours undergoing cardioversion: value of transesophageal echocar- diography to guide cardioversion. J Am Soc Echocardiogr. 2009;22(12):1403-1408. 160. Flaker GC, Belew K, Beckman K, et al; AFFIRM Investi- gators. Asymptomatic atrial brillation: demographic fea- tures and prognostic information from the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. Am Heart J. 2005;149(4):657-663. 161. Weigner MJ, Caul eld TA, Danias PG, Silverman DI, Manning WJ. Risk for clinical thromboembolism associ- ated with conversion to sinus rhythm in patients with atrial brillation lasting less than 48 hours. Ann Intern Med. 1997;126(8):615-620. 162. Arnold AZ, Mick MJ, Mazurek RP, Loop FD, Trohman RG. Role of prophylactic anticoagulation for direct current car- dioversion in patients with atrial brillation or atrial utter. J Am Coll Cardiol. 1992;19(4):851-855. 163. Chalasani P, Cambre S, Silverman ME. Direct-current car- dioversion for the conversion of atrial utter. Am J Cardiol. 1996;77(8):658-660. 164. Hart RG, Benavente O, McBride R, Pearce LA. Anti- thrombotic therapy to prevent stroke in patients with atrial brillation: a meta-analysis. Ann Intern Med. 1999;131(7): 492-501. 165. Fang MC, Chang Y, Hylek EM, et al. Advanced age, anti- coagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial brillation.


Advanced age, anti- coagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial brillation. Ann Intern Med. 2004;141(10):745-752. 166. Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial brillation. N Engl J Med. 2003;349(11):1019-1026. 167. Hylek EM, Skates SJ, Sheehan MA, Singer DE. An analysis of the lowest effective intensity of prophylactic anticoagula- tion for patients with nonrheumatic atrial brillation. N Engl J Med. 1996;335(8):540-546. 168. Walker AM, Bennett D. Epidemiology and outcomes in patients with atrial brillation in the United States. Heart Rhythm. 2008;5(10):1365-1372. 169. Singer DE, Chang Y, Fang MC, et al. Should patient char- acteristics in uence target anticoagulation intensity for stroke prevention in nonvalvular atrial brillation?: the ATRIA study. Circ Cardiovasc Qual Outcomes. 2009;2(4): 297-304. 170. Rose AJ, Ozonoff A, Henault LE, Hylek EM. Warfarin for atrial brillation in community-based practise. J Thromb Haemost. 2008;6(10):1647-1654. 171. Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical prac- tice guidelines. Chest. 2012;141(2)(suppl):e44S-e88S. 172. Jones M, McEwan P, Morgan CL, Peters JR, Goodfellow J, Currie CJ. Evaluation of the pattern of treatment, level of anticoagulation control, and outcome of treatment with warfarin in patients with non-valvar atrial brillation: a record linkage study in a large British population. Heart. 2005;91(4):472-477. 173. White HD, Gruber M, Feyzi J, et al. Comparison of out- comes among patients randomized to warfarin therapy according to anticoagulant control: results from SPORTIF III and V. Arch Intern Med. 2007;167(3):239-245. 174. Connolly SJ, Pogue J, Eikelboom J, et al; ACTIVE W Investigators.


Connolly SJ, Pogue J, Eikelboom J, et al; ACTIVE W Investigators. Bene t of oral anticoagulant over antiplate- let therapy in atrial brillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation. 2008;118(20):2029-2037. 175. Wan Y, Heneghan C, Perera R, et al. Anticoagulation control and prediction of adverse events in patients with atrial bril- lation: a systematic review. Circ Cardiovasc Qual Outcomes. 2008;1(2):84-91.


Note: Authors from the National Institutes of Health/National Heart, Lung, and Blood Institute represent themselves and not the opinions of the National Institutes of Health/National Heart, Lung, and Blood Institute. The American Heart Association, the American College of Cardiology, and American Society of Hypertension make every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest. This document was approved by the American Heart Association Science Advisory and Coordinating Committee on September 22, 2014, by the American College of Cardiology on October 10, 2014, and by the American Society of Hypertension on September 30, 2014. The American Heart Association requests that this document be cited as follows: Rosendorff C, Lackland DT, Allison M, Aronow WS, Black HR, Blumenthal RS, Cannon CP, de Lemos JA, Elliott WJ, Findeiss L, Gersh BJ, Gore JM, Levy D, Long JB, O Connor CM, O Gara PT, Ogedegbe G, Oparil S, White WB; on behalf of the American Heart Association, American College of Cardiology, and American Society of Hypertension. Treatment of hypertension in patients with coronary artery disease: a scientific statement from the American Heart Association, American College of Cardiology, and American Society of Hypertension. Hypertension. 2015;65:1372 1407. This article has been copublished in Circulation, the Journal of the American College of Cardiology, and the Journal of the American Society of Hypertension.


This article has been copublished in Circulation, the Journal of the American College of Cardiology, and the Journal of the American Society of Hypertension. Copies: This document is available on the World Wide Web sites of the American Heart Association (my.americanheart.org), the American College of Cardiology (www.cardiosource.org), and the American Society of Hypertension (http://www.ash-us.org/). A copy of the document is available at http:// my.americanheart.org/statements by selecting either the By Topic link or the By Publication Date link. To purchase additional reprints, call 843-216- 2533 or e-mail kelle.ramsay@wolterskluwer.com. Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http://my.americanheart.org/statements and select the Policies and Development link. Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/Copyright- Permission-Guidelines_UCM_300404_Article.jsp. A link to the Copyright Permissions Request Form appears on the right side of the page. 2015 by the American Heart Association, Inc., the American College of Cardiology Foundation, and American Society of Hypertension, Inc. Treatment of Hypertension in Patients With Coronary Artery Disease A Scientific Statement From the American Heart Association, American College of Cardiology, and American Society of Hypertension Clive Rosendorff, MD, PhD, DScMed, FAHA, FACC, FASH, Chair; Daniel T. Lackland, DrPH, FAHA, FASH, Co-Chair; Matthew Allison, MD, FAHA; Wilbert S. Aronow, MD, FAHA, FACC; Henry R. Black, MD, FAHA, FASH; Roger S. Blumenthal, MD, FAHA, FACC; Christopher P. Cannon, MD, FAHA, FACC; James A. de Lemos, MD, FAHA, FACC; William J. Elliott, MD, PhD, FASH; Laura Findeiss, MD, FAHA; Bernard J. Gersh, MB ChB, DPhil, FAHA, MACC; Joel M. Gore, MD, FAHA, FACC; Daniel Levy, MD, FACC; Janet B.


Treatment of Hypertension in Patients With Coronary Artery Disease A Scientific Statement From the American Heart Association, American College of Cardiology, and American Society of Hypertension Clive Rosendorff, MD, PhD, DScMed, FAHA, FACC, FASH, Chair; Daniel T. Lackland, DrPH, FAHA, FASH, Co-Chair; Matthew Allison, MD, FAHA; Wilbert S. Aronow, MD, FAHA, FACC; Henry R. Black, MD, FAHA, FASH; Roger S. Blumenthal, MD, FAHA, FACC; Christopher P. Cannon, MD, FAHA, FACC; James A. de Lemos, MD, FAHA, FACC; William J. Elliott, MD, PhD, FASH; Laura Findeiss, MD, FAHA; Bernard J. Gersh, MB ChB, DPhil, FAHA, MACC; Joel M. Gore, MD, FAHA, FACC; Daniel Levy, MD, FACC; Janet B. Long, MSN, FAHA; Christopher M. O Connor, MD, FACC; Patrick T. O Gara, MD, FAHA, FACC; Gbenga Ogedegbe, MD, MPH, FASH; Suzanne Oparil, MD, FAHA, FACC, FASH; William B. White, MD, FAHA, FASH; on behalf of the American Heart Association, American College of Cardiology, and American Society of Hypertension AHA/ACC/ASH Scientific Statement Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYP.0000000000000018 Table of Contents 1. Relationship Between Hypertension and CAD 1374 1.1. Epidemiology of Hypertension and CAD 1374 1.1.1. Effects of Treatment 1374 1.1.2. Risk Factor Interactions 1376 1.1.3. Risk Factor Reduction 1376 1.1.4. Dyslipidemia 1376 1.1.5. Diabetes Mellitus 1377 1.1.6. Smoking 1377 1.1.7. Obesity 1377 1.1.8. Peripheral Artery Disease 1377 1.1.9. Chronic Kidney Disease 1378 1.2. Mechanisms of Hypertension and CAD 1378 1.2.1. Genetics 1378 1.2.2. Physical Forces and Hemodynamics 1378 1.2.3. Endothelial Dysfunction 1379 1.2.4. Oxidative Stress 1379 1.2.5. Humoral and Metabolic Factors 1379 1.2.6.


Oxidative Stress 1379 1.2.5. Humoral and Metabolic Factors 1379 1.2.6. Calcium 1380 Rosendorff et al Treatment of Hypertension in Patients With CAD 1373 This is an update of the American Heart Association (AHA) scientific statement Treatment of Hypertension in the Prevention and Management of Ischemic Heart Disease: A Scientific Statement From the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention, published in 2007.1 A number of important studies have been published since that date that serve to modify or at least to further refine the recommendations of that statement, so an update was considered appropriate and timely. Because an AHA/American College of Cardiology (ACC)/American Society of Hypertension guideline on the treatment of hyper- tension in primary prevention is in process, this document is concerned with the epidemiology of hypertension and its treatment in secondary prevention, specifically in the setting of coronary artery disease (CAD). Epidemiological studies have established a strong asso- ciation between hypertension and CAD. Hypertension is a major independent risk factor for the development of CAD, stroke, and renal failure. The optimal choice of antihyperten- sive agents remains controversial, and there are only partial answers to important questions in the treatment of hyperten- sion for the prevention and management of ischemic heart disease (IHD): What are the appropriate systolic blood pressure (SBP) and diastolic blood pressure (DBP) targets in patients with established CAD? Are the beneficial effects of treatment simply a function of blood pressure (BP) lowering, or do particular classes of drugs have uniquely protective actions in addition to lowering BP? Are there antihypertensive drugs that have shown par- ticular efficacy in the secondary prevention of IHD?


Are there antihypertensive drugs that have shown par- ticular efficacy in the secondary prevention of IHD? Which antihypertensive drugs should be used in patients who have established CAD with stable angina pectoris, in those with acute coronary syndrome (ACS), which in- cludes unstable angina pectoris (UA), non ST-segment elevation myocardial infarction (NSTEMI), and ST- elevation myocardial infarction (STEMI), and in those with heart failure (HF) caused by CAD? This scientific statement summarizes the published data relating to the treatment of hypertension in the context of Prevention of Cardiovascular Events in Patients With Hypertension and CAD 1380 Antihypertensive Drugs for the Secondary Prevention of Cardiovascular Events in Patients With CAD 1380 Thiazide and Thiazide-Type Diuretics 1380 -Blockers 1380 2.1.3. ACE Inhibitors 1380 Angiotensin Receptor Blockers 1381 2.1.5. Aldosterone Antagonists 1381 Calcium Channel Blockers 1382 Direct Renin Inhibitors 1382 3. BP Goals 1382 Epidemiology and Coronary Physiology 1382 3.1.1. Epidemiological Studies 1382 3.1.2. Coronary Perfusion, Autoregulation, and the J-curve 1382 3.2. Clinical Studies 1383 Lower BP With a Surrogate Outcome 1383 Observational Studies and Clinical Trials 1383 Clinical Trials to Specifically Evaluate Lower BP Goals 1384 Lower BP Goals and Diabetes Mellitus . 1384 Lower BP Goals for the Prevention of Stroke 1385 3.2.6. The Elderly 1385 3.2.7. Conclusions 1385 3.3. Recommendations 1386 Management of Hypertension in Patients With CAD and Stable Angina 1386 4.1. Pharmacological Therapy 1386 -Blockers 1386 Calcium Channel Blockers 1386 4.1.3. ACE Inhibitors 1387 Angiotensin Receptor Blockers 1387 4.1.5. Diuretics 1387 4.1.6. Nitrates 1388 4.2.  Recommendations 1388 Management of Hypertension in Patients With ACS 1388 5.1. Prevalence and Impact on Prognosis 1388 General Principles of BP Management in the Patient With ACS 1389 5.3. Specific Antihypertensive Agents in ACS 1389 5.3.1. Nitroglycerin 1389 -Blockers 1390 Calcium Channel Blockers 1390 5.3.4.


Specific Antihypertensive Agents in ACS 1389 5.3.1. Nitroglycerin 1389 -Blockers 1390 Calcium Channel Blockers 1390 5.3.4. ACE Inhibitors 1390 Angiotensin Receptor Blockers 1391 5.3.6. Aldosterone Antagonists 1391 5.3.7. Diuretics 1391 Safety of Anticoagulation in Patients With Uncontrolled Hypertension 1391 5.5. Conclusions 1391 5.6. Recommendations 1392 Management of Hypertension in HF of Ischemic Origin 1392 Hypertension and HF 1392 6.2. Demographics 1392 Hypertension and HF Pathophysiology 1393 CAD and Acute HF 1393 6.5. Therapeutic Strategies 1393 6.6. Nonpharmacological Therapies 1393 6.7. Pharmacological Therapies 1393 6.7.1. Diuretics 1393 6.7.2. ACE Inhibitors 1394 Angiotensin Receptor Blockers 1394 -Blockers 1394 Nitrates and Hydralazine 1395 6.7.6. Aldosterone Receptor Antagonists 1395 6.8. Renal Denervation 1395 6.9. Goal BP 1395 6.10. Drugs to Avoid 1395 6.11. Recommendations 1396 CAD prevention and management. It attempts, on the basis of the best available evidence, to develop recommendations that will be appropriate for both BP reduction and the man- agement of CAD in its various manifestations. When data are meager or lacking, the writing group has proposed consensus recommendations and has highlighted opportunities for well- designed prospective clinical trials to fill knowledge gaps. All of the discussion and recommendations refer to adults. The writing committee has not addressed hypertension or IHD in the pediatric age group. In addition, there is no discussion of the different modes of assessing BP, including 24-hour ambulatory BP monitoring. These were the subject of an AHA scientific statement in 2005.2 Recommendations, with levels of evidence, have been developed according to the AHA format shown in Table 1. The general design of the scientific statement is based on the concept that each of the clinical sections refers to a particular subset of patients, so each section should pro- vide a stand-alone description of the recommendations and their justification independently of the other sections.


The general design of the scientific statement is based on the concept that each of the clinical sections refers to a particular subset of patients, so each section should pro- vide a stand-alone description of the recommendations and their justification independently of the other sections. This should make it easier for practitioners to extract the infor- mation relevant to any particular patient without needing to cross-reference, and we hope it will thereby increase the utility of this document. With this organization, there may be some repetition of information from one section to the next, but we have tried to keep that to a minimum. A summary of the main recommendations is presented in Tables 2 and 3. 1. Relationship Between Hypertension and CAD 1.1. Epidemiology of Hypertension and CAD Hypertension is a major independent risk factor for CAD for all age/race/sex groups. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure3 uses the traditional definition of hypertension as an SBP of 140 mmHg or a DBP of 90 mmHg and/or the current use of antihyperten- sive medication. With this definition, an estimated 65 million adult Americans, or nearly one fourth of the adult population of the United States, have hypertension.Another quarter of the population have prehypertension, defined as an SBP of 120 to 139 mmHg or a DBP of 80 to 89 mmHg. The forms of BP elevation differ as a function of age, with DBP elevation predominating in young hypertensive indi- viduals and systolic hypertension, often in isolation (isolated systolic hypertension), emerging in older age. The prevalence of hypertension is thus directly proportional to the age of the population, with more than half of Americans >65 years of age having a high BP.


The prevalence of hypertension is thus directly proportional to the age of the population, with more than half of Americans >65 years of age having a high BP. The Framingham Heart Study has esti- mated the remaining lifetime risk of developing hypertension at 90% for men and women not yet hypertensive by middle In addition, there is a change with age in the relative importance of SBP and DBP as risk indicators. Before 50 years of age, DBP is the major predictor of IHD risk, whereas after 60 years of age, SBP is more important.5 It is important to note that, in this population 60 years of age, DBP becomes inversely related to CAD risk and pulse pressure becomes the strongest predictor for CAD. In a meta-analysis of 61 studies that included almost 1 million adults,6 BP was related to fatal CAD over the BP range of 115/75 to 185/115 mmHg for all ages. Overall, each increase in SBP of 20 mmHg (or each 10-mmHg increase in DBP) doubles the risk of a fatal coro- nary event. Epidemiological studies have also shown that an elevated BP is the most important determinant of the risk of stroke. The risk is almost linear, beginning at relatively low levels of SBP and DBP,7 and the lowering of high BP is a major factor in the impressive reduction in the stroke death rates during the last half of the 20th century and the early part of the 21st The absolute risk of these adverse outcomes also increases with age.


The risk is almost linear, beginning at relatively low levels of SBP and DBP,7 and the lowering of high BP is a major factor in the impressive reduction in the stroke death rates during the last half of the 20th century and the early part of the 21st The absolute risk of these adverse outcomes also increases with age. For any given SBP, the risk of fatal CAD was 16- fold higher for people 80 to 89 years of age than for those In the Chicago Heart Association Detection Project in Industry, men 18 to 39 years of age at baseline with a BP of 130 to 139/85 to 89 mm Hg or with stage 1 hypertension (140 159/90 99 mm Hg) accounted for nearly 60% of all excess IHD, overall cardiovascular disease (CVD), or all-cause mortality.9 Epidemiological data show that lower BP levels are associated with lower disease risks, suggesting that future coronary events can be prevented by reducing BP.10 Elevated BP represents a sub- stantial population-attributable risk for men and women, both black and white.11,12 1.1.1. Effects of Treatment The risk of CVD in the patient with hypertension has been shown to be greatly reduced with effective antihypertensive therapy. Major reductions in CVD morbidity and mortality over the past 50 years have been attributed to the increased availability and use of drug treatment for hypertension. Randomized trials have shown that BP lowering in patients with hypertension produces rapid reductions in cardiovascu- that are highly consistent with data from observa- tional studies.


Randomized trials have shown that BP lowering in patients with hypertension produces rapid reductions in cardiovascu- that are highly consistent with data from observa- tional studies. For example, a 10-mmHg lower usual SBP (or a 5-mmHg lower usual DBP) is associated with a 50% to 60% lower risk of stroke death and an 40% to 50% lower risk of death resulting from CAD or other vascular causes at middle age, benefits that are only slightly smaller in older However, in one study, high blood pressure in the very elderly (>85 years) was not a risk factor for mortal- ity, irrespective of a history of hypertension. Whereas blood pressure values below 140/70 mm Hg were associated with Likewise, there are inconsistencies across end points in the older population, with a significant associa- tion of lower BP with lower stroke deaths and HF but not with a lower rate of myocardial infarction (MI) in patients Several studies (Heart Outcomes Prevention Evaluation Survival and Ventricular Enlargement [SAVE],17 and European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease [EUROPA])18 have shown a beneficial effect of angiotensin-converting enzyme (ACE) inhibitors on CVD outcomes in individuals, some hypertensive and some not, but all with established CVD or at high risk for its development. However, we do not yet have outcome studies of treatment of prehypertension Rosendorff et al Treatment of Hypertension in Patients With CAD 1375 in individuals with BPs in the range of 130 to 139/80 to 89 mmHg.


However, we do not yet have outcome studies of treatment of prehypertension Rosendorff et al Treatment of Hypertension in Patients With CAD 1375 in individuals with BPs in the range of 130 to 139/80 to 89 mmHg. The only prospective clinical trial of BP reduction in individuals with normal BPs is the Trial of Preventing Hypertension (TROPHY) study,19 in which subjects with an SBP of 130 to 139 mmHg or a DBP of 85 to 89 mmHg were randomized to be treated for 2 years with either the angio- tensin receptor blocker (ARB) candesartan or placebo and followed up for an additional 2 years. Hypertension devel- oped in significantly (P<0.007) more participants in the pla- cebo group (two thirds of this cohort at 4 years) than in the candesartan group, with a relative risk reduction of 66.3% at 2 years and 15.6% at 4 years. In addition, the treatment of prehypertension with candesartan appeared to be well toler- ated, and serious adverse events occurred in 3.5% and 5.9% in patients treated with candesartan and placebo, respectively. However, the study was not designed or powered to assess CVD outcomes. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, with a mean follow-up of 4.7 years, a tar- get BP of <120 compared with <140 mmHg was not associ- ated with a reduced risk of a composite of CVD events (heart attack, a stroke, or a cardiovascular death).20 However, the incidence of stroke was significantly less in the intensively treated group. Table 1. Applying Classification of Recommendations and Levels of Evidence. A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials.


Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Although randomized trials are unavailable, there may be a very clear clinical consensus that a particular test or therapy is useful or effective. *Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as sex, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use. For comparative effectiveness recommendations (Class I and IIa; Level of Evidence A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated. 1.1.2. Risk Factor Interactions Data from the Framingham Heart Study have provided evi- dence of a predictive role of hypertension, dyslipidemia, glucose intolerance, cigarette smoking, and left ventricular (LV) hypertrophy in CVD.21 These 5 primary risk factors are the most important modifiable determinants of CVD risk and appear to operate independently of one another. This has led to the idea that the threshold at which a patient should be treated for hypertension should be determined by a patient s burden of CVD risk factors, which in turn deter- mine the level of CVD risk. In the guidelines developed by the National Kidney Foundation,22 this principle has been followed for patients with albuminuria and even modest chronic renal insufficiency, for which the BP threshold for the initiation of antihypertensive therapy is 130/80 mm Hg. The American Diabetes Association has based its recom- mendation on age: People with diabetes mellitus should be treated to a BP of <140/80 mm Hg, except that lower systolic targets, such as <130 mm Hg, may be appropri- ate for certain individuals, such as younger patients, if it can be achieved without undue treatment burden.


The American Diabetes Association has based its recom- mendation on age: People with diabetes mellitus should be treated to a BP of <140/80 mm Hg, except that lower systolic targets, such as <130 mm Hg, may be appropri- ate for certain individuals, such as younger patients, if it can be achieved without undue treatment burden. 23 Furthermore, there is a correlation between hypertension and body mass index, with both strongly correlated with CAD. Hypertension and abdominal obesity are components of a larger risk factor constellation of cardiovascular risk factors, the metabolic syndrome, which also includes a characteristic form of dyslipidemia (high triglycerides and low high-density lipoprotein cholesterol) and an elevated fasting blood glucose level.24 1.1.3. Risk Factor Reduction Hypertension, dyslipidemia, diabetes mellitus, cigarette smoking, obesity, and chronic kidney disease (CKD) are independent determinants of CVD risk. Moreover, a diagno- sis of peripheral artery disease (PAD) significantly increases the risk for both prevalent and incident disease in other vascular beds including the coronary and cerebral circula- As indicated previously, hypertension represents an independent risk factor for CVD, and evidence indicates that the concomitant presence of other recognized cardiovascu- lar risk factors results in a multiplicative increase in risk for cardiovascular events. Some current guidelines call for more aggressive BP management in the presence of other cardio- vascular risk factors, and BP reduction without attention to other risk factors is inadequate to reduce cardiovascular risk. Readers should be aware that several recently published guideline documents detail the strategies for risk assessment and management.


Readers should be aware that several recently published guideline documents detail the strategies for risk assessment and management. The recommendations in this document reflect the published guidelines, but readers are advised to consult other recent guidelines such as those on the assess- ment of cardiovascular risk,27 lifestyle management, particu- larly as it relates to diet and exercise,28 and the management Cardiovascular risk factors may be described as nonmodifi- able or modifiable. The nonmodifiable risk factors of age, sex, race/ethnicity, and genetic predisposition/family history are not addressed in this report. The potentially modifiable risk factors include dyslipidemia, diabetes mellitus, smoking, obe- sity, PAD, and renal insufficiency. The management of dyslipidemia was the subject of a recent In essence, the new guideline does not support continued use of specific low-density lipoprotein (LDL) cholesterol or non high-density lipoprotein cholesterol treatment targets. The guideline advocates the use of a 10-year risk calculator to Table 2. Summary of Pharmacological Treatment of Hypertension in the Management of Ischemic Heart Disease. ACEI or ARB Diuretic -Blocker Non-DHP CCB DHP CCB Nitrates Aldosterone Antagonist Hydralazine/ Isosorbide Dinitrate ACEI indicates angiotensin-converting enzyme inhibitor; ACS, acute coronary syndrome; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; DHP, dihydropyridine; HF, heart failure; 1, drug of choice; and 2, add-on, alternative drug, or special indications. *Especially if prior myocardial infarction, left ventricular systolic dysfunction, diabetes mellitus, or proteinuric chronic kidney disease is present. Chlorthalidone is preferred. Loop diuretic should be used in the presence of HF (New York Heart Association class III or IV) or chronic kidney disease with glomerular . Caution should be exercised in HF with preserved ejection fraction. If -blocker is contraindicated, a non-DHP CCB can be substituted, but not if left ventricular dysfunction or HF is present.


If -blocker is contraindicated, a non-DHP CCB can be substituted, but not if left ventricular dysfunction or HF is present. Caution should be exercised if combining a non-DHP CCB with a -blocker. Esmolol (intravenous) or metoprolol or bisoprolol (oral). Spironolactone or eplerenone if left ventricular dysfunction, HF, or diabetes mellitus is present. Carvedilol, metoprolol succinate, or bisoprolol. Table 3. Summary of BP Goals BP Goal, mmHg Condition Class/Level of Evidence <140/90 CAD IIa/B ACS IIa/C HF IIa/B <130/80 CAD IIb/B Post myocardial infarction, stroke or TIA, carotid artery disease, PAD, AAA IIb/B AAA indicates abdominal aortic aneurysm; ACS, acute coronary syndrome; BP, blood pressure; CAD, coronary artery disease; HF, heart failure; PAD, peripheral arterial disease; and TIA, transient ischemic attack. Rosendorff et al Treatment of Hypertension in Patients With CAD 1377 determine the appropriate intensity of statin therapy to reduce CVD risk in those most likely to benefit. Those patients with CVD and age 75 years, with LDL cholesterol 190 mg/dL, or with a 10-year CVD risk 7.5% should receive high- intensity statin therapy (eg, atorvastatin 40 80 mg/d or rosuvastatin 20 40 mg/d to reduce LDL cholesterol by approximately 50%). Those with CVD who are >75 years of age or those with diabetes mellitus but with a 10-year risk of <7.5% should receive moderate-intensity statin therapy such as simvastatin 20 to 40 mg/d, atorvastatin 10 to 20 mg/d, or rosuvastatin 5 to 10 mg/d to decrease LDL cholesterol by 30% to 50%. According to the guideline, nonstatin therapies do not provide acceptable CVD risk reduction benefits compared with their potential for adverse effects in the routine prevention of CVD. 1.1.5.


According to the guideline, nonstatin therapies do not provide acceptable CVD risk reduction benefits compared with their potential for adverse effects in the routine prevention of CVD. 1.1.5. Diabetes Mellitus Type 2 diabetes mellitus is defined as a fasting plasma glucose 126 mg/dL, a 2-hour oral glucose tolerance test value 200 mg/dL, hemoglobin A1C 6.5%, or random plasma glucose 200 mg/dL in a patient with classic symptoms of hypergly- Type 2 diabetes mellitus is a strong and independent risk factor for coronary heart disease. So strong is this associa- tion that a diagnosis of diabetes mellitus could be considered a coronary heart disease risk equivalent,24 although this is con- Hypertensive patients with type 2 diabetes mel- litus are also at increased risk for diabetes mellitus specific complications, including retinopathy and nephropathy. The pharmacological management of diabetes mellitus is beyond the scope of this review. Diabetes mellitus care is complex and requires that many issues, beyond glycemic con- trol, be addressed. There is general consensus that smoking increases the risk of cardiovascular events. Many studies have shown a correlation between smoking and death. Life expectancy is reduced by 13.2 years in male smokers compared with nonsmokers, and this trend is stronger in female smokers, with a 14.5-year decrease in life expectancy.32 Cigarette smoking independently predicts increased risk of cardiac arrest in patients with CAD,33 and even exposure to secondhand smoke increases the risk of develop- ing CAD by 25% to 30%.34 As with other risk factors, there is a synergistic increase in cardiovascular risk in smokers who have other, concurrent, cardiovascular risk factors.


Life expectancy is reduced by 13.2 years in male smokers compared with nonsmokers, and this trend is stronger in female smokers, with a 14.5-year decrease in life expectancy.32 Cigarette smoking independently predicts increased risk of cardiac arrest in patients with CAD,33 and even exposure to secondhand smoke increases the risk of develop- ing CAD by 25% to 30%.34 As with other risk factors, there is a synergistic increase in cardiovascular risk in smokers who have other, concurrent, cardiovascular risk factors. Elevated cholesterol confers a higher risk of cardiovascular events in smokers than in nonsmokers, and smokers disproportionately tend toward unfavorable lipoprotein profiles.35 In patients with hypertension, smokers are 5 times more likely to develop severe hypertension than nonsmokers, and smokers with severe hyper- tension have higher mortality rates than nonsmokers.36 It is encouraging that studies of smoking cessation dem- onstrate significant long-term reduction (15% over 14 years) in mortality in patients who participate in smoking cessation The prevalence of obesity, defined as a body mass index 30 , has increased in recent years, with 30% of the adult US population falling into this category.38 The positive rela- tionship between obesity and BP is well documented.39 41 Obese adults are 3 times more likely to be hypertensive compared with nonobese adults,40 42 and increased adiposity may explain >60% of hypertension in adults.40 Furthermore, obesity is considered a major risk factor for poor BP control in hypertensive patients.3 Although the mechanisms of obesity-related hypertension are numerous, including activation of the sympathetic nervous system, sodium retention, activation of the renin-angiotensin- aldosterone system (RAAS), insulin resistance, and altered there is no acceptable guideline on the antihypertensive drug of choice for the management of hyper- tension among obese patients.3,44 Some investigators consider ACE inhibitors the drugs of choice for adequate BP control in obesity-related hyperten- sion because of their capacity to increase insulin sensitivity and thus reduce the risk of diabetes mellitus.45 This is in con- trast to thiazide diuretics, which are associated with increased risk of diabetes mellitus.46 That said, the efficacy of thiazide diuretics in lowering BP and improving cardiovascular out- comes in obese hypertensive patients is well established.47 -Blockers also have adverse effects on glucose metabo- lism but have led to significant improvement in BP in obese hypertensive patients because they decrease renin activity and cardiac output, which are often elevated in obese patients.48 However, enthusiasm for the use of -blockers as initial ther- apy is largely dampened by their negative profile on stroke outcomes compared with placebo and other antihypertensive There is abundant evidence in support of the effectiveness of lifestyle interventions in improving BP control among obese hypertensive patients.


Recently, the AHA, ACC, and Obesity Society have published guidelines29 for the manage- ment of overweight and obesity in adults, including identi- fying patients who need to lose weight, matching treatment benefits with risk profiles, diets for weight loss, lifestyle inter- vention and counseling, and the selection of patients for bar- iatric surgery. There is also much useful information, particularly on diet and physical activity, in another AHA/ACC guidelines docu- ment on lifestyle management.28 1.1.8. Peripheral Artery Disease Treatment of hypertension in patients with PAD is associated with a significant reduction in the risk of MI, stroke, HF, and death. Similarly, intensive management of LDL is associated with significant reduction of cardiovascular events in patients Thus, management of hypertension in patients with PAD should be based on intensive screening for and aggressive management of other concomitant cardiovascular risk factors in addition to BP reduction.3 Particularly impor- tant in this regard is the management of dyslipidemia, smoking cessation, antiplatelet therapy, diabetes mellitus management, diet, and exercise. Currently, there is no recommended drug of choice for the treatment of hypertension in patients with PAD because clinical trials of antihypertensive drug agents such as ACE inhibitors, calcium channel blockers (CCBs), -adrenergic blockers, and direct vasodilators have been largely unsuccess- ful in improving symptoms of claudication or walking dis- tance in patients with PAD.51 53 Although -blockers constrict resistance vessels, a meta-analysis concluded that this drug class does not worsen intermittent claudication in patients with intermittent claudication.54 Thus, -blockers can be used in PAD patients with compelling indications for their use such as CAD or HF.


Currently, there is no recommended drug of choice for the treatment of hypertension in patients with PAD because clinical trials of antihypertensive drug agents such as ACE inhibitors, calcium channel blockers (CCBs), -adrenergic blockers, and direct vasodilators have been largely unsuccess- ful in improving symptoms of claudication or walking dis- tance in patients with PAD.51 53 Although -blockers constrict resistance vessels, a meta-analysis concluded that this drug class does not worsen intermittent claudication in patients with intermittent claudication.54 Thus, -blockers can be used in PAD patients with compelling indications for their use such as CAD or HF. The recommendations of the ACC/AHA 2005 prac- tice guidelines on PAD55 include the following: (1) Antihypertensive therapy should be administered to hyperten- sive patients with lower-extremity PAD to achieve a goal of <140/90 mmHg (nondiabetics) or <130/80 mmHg (diabetics and individuals with chronic renal disease) to reduce the risk of MI, stroke, congestive HF, and cardiovascular death (Level of Evidence A); (2) -adrenergic blocking drugs are effective antihypertensive agents and are not contraindicated in patients with PAD (Level of EvidenceA); (3) the use ofACE inhibitors orARBs is reasonable for patients with symptomatic (Level of Evidence B) or asymptomatic (Level of Evidence C) leg PAD. 1.1.9.


The recommendations of the ACC/AHA 2005 prac- tice guidelines on PAD55 include the following: (1) Antihypertensive therapy should be administered to hyperten- sive patients with lower-extremity PAD to achieve a goal of <140/90 mmHg (nondiabetics) or <130/80 mmHg (diabetics and individuals with chronic renal disease) to reduce the risk of MI, stroke, congestive HF, and cardiovascular death (Level of Evidence A); (2) -adrenergic blocking drugs are effective antihypertensive agents and are not contraindicated in patients with PAD (Level of EvidenceA); (3) the use ofACE inhibitors orARBs is reasonable for patients with symptomatic (Level of Evidence B) or asymptomatic (Level of Evidence C) leg PAD. 1.1.9. Chronic Kidney Disease There has been a steady increase in the prevalence of CKD, defined as kidney damage, documented by kidney biopsy or serum markers for 3 months, or a decrease in glomerular filtration rate to <60 mL min 1 Kidney failure, defined as a glomerular filtration rate of <15 , and end-stage renal disease, which neces- sitates the initiation of treatment by replacement therapy,22 afflicts >525000 patients in the United States, 65% of whom are on long-term hemodialysis.56 Hypertension represents a major independent risk factor for renal failure, with a preva- lence of 28% in hypertensive patients.56 In patients with CKD, cardiovascular death is more likely than progression to end- stage renal disease, and in patients with end-stage renal dis- ease, CVD is the leading cause of death, being 5 to 30 times higher in patients on dialysis than in the general population.57 Even in patients with lower stages of CKD, the risk of CVD is increased independently of other risk factors, and even the smallest degree of albuminuria increases risk for CVD and all- In this patient population, hypertension itself is a leading cause of renal failure.


Chronic Kidney Disease There has been a steady increase in the prevalence of CKD, defined as kidney damage, documented by kidney biopsy or serum markers for 3 months, or a decrease in glomerular filtration rate to <60 mL min 1 Kidney failure, defined as a glomerular filtration rate of <15 , and end-stage renal disease, which neces- sitates the initiation of treatment by replacement therapy,22 afflicts >525000 patients in the United States, 65% of whom are on long-term hemodialysis.56 Hypertension represents a major independent risk factor for renal failure, with a preva- lence of 28% in hypertensive patients.56 In patients with CKD, cardiovascular death is more likely than progression to end- stage renal disease, and in patients with end-stage renal dis- ease, CVD is the leading cause of death, being 5 to 30 times higher in patients on dialysis than in the general population.57 Even in patients with lower stages of CKD, the risk of CVD is increased independently of other risk factors, and even the smallest degree of albuminuria increases risk for CVD and all- In this patient population, hypertension itself is a leading cause of renal failure. BP goals in patients with CKD and microalbuminuria are lower than in the general popula- with a target the same as that in patients with estab- lished CAD. Recent investigations have demonstrated that standard treatments for cardiovascular risk factors, including statin therapy, ACE inhibitors, ARBs, and antiplatelet agents, are equally effective at risk reduction in patients with CKD (who are not on dialysis) as in those without CKD and should be offered to this patient population.59 In these patients, the serum potassium concentration should be monitored fre- quently.


Recent investigations have demonstrated that standard treatments for cardiovascular risk factors, including statin therapy, ACE inhibitors, ARBs, and antiplatelet agents, are equally effective at risk reduction in patients with CKD (who are not on dialysis) as in those without CKD and should be offered to this patient population.59 In these patients, the serum potassium concentration should be monitored fre- quently. Questions remain as to whether directly addressing nontraditional risk factors in patients with early evidence of renal impairment has efficacy in terms of outcomes. 1.2. Mechanisms of Hypertension and CAD A variety of pathophysiological mechanisms contribute to the genesis of BP elevation and related target-organ dam- age, including CAD. These mechanisms include increased sympathetic nervous system and RAAS activity; deficiencies in the release or activity of vasodilators, for example, nitric oxide and prostacyclin, and changes in the natriuretic peptide concentration; increased expression of growth factors and inflammatory cytokines in the arterial tree; hemodynamic effects; and structural and functional abnormalities in conduc- tance and resistance arteries, particularly increased vascular stiffness and endothelial dysfunction.60 These neurohumoral pathways interact with genetic, demographic, and environ- mental factors (such as heightened exposure or response to psychosocial stress, excessive dietary intake of sodium, and inadequate dietary intake of potassium and calcium) to deter- mine whether a person will develop hypertension and related CAD. Concomitant metabolic disorders, for example, diabe- tes mellitus, insulin resistance, and obesity, also lead to the production of vasoactive adipocytokines that promote vaso- constriction, endothelial dysfunction, inflammation, and increased oxidative stress in the vasculature, thus increasing both BP and CVD risk.61,62 These shared pathophysiological mechanisms offer potential novel therapeutic targets for the prevention and treatment of both hypertension and CAD, with benefits that may go beyond BP lowering.


Concomitant metabolic disorders, for example, diabe- tes mellitus, insulin resistance, and obesity, also lead to the production of vasoactive adipocytokines that promote vaso- constriction, endothelial dysfunction, inflammation, and increased oxidative stress in the vasculature, thus increasing both BP and CVD risk.61,62 These shared pathophysiological mechanisms offer potential novel therapeutic targets for the prevention and treatment of both hypertension and CAD, with benefits that may go beyond BP lowering. Genome-wide association studies have identified multiple genetic susceptibility variants, mostly single-nucleotide poly- morphisms, for atherosclerotic disease.63 It has been suggested the polymorphisms of genes of the RAAS, particularly ACE, angiotensin II receptor type 1, and angiotensinogen, are impli- cated in the development of CAD and MI.64,65 The presence of hypertension further increases the risk of CAD and may explain why some individuals are more predisposed than oth- ers to developing coronary events. Some polymorphisms have also been implicated in the BP response to antihypertensive treatment. For example, genetic polymorphisms coding for the matrix metalloproteinases appear to modify CVD outcomes in hypertensive patients treated with chlorthalidone, amlodipine, These data suggest that, in the future, determi- nation of genetic variants may be of some use for selecting appropriate antihypertensive agents to reduce both BP and the risk for CAD. However, because CAD is polygenic and its causes are multifactorial, genetic studies explain only a small proportion of the heritability of the disease.67 1.2.2. Physical Forces and Hemodynamics Physical forces (pressure and flow) are the primary determi- nants of cardiac structure and function and influence coro- nary arterial remodeling and atherosclerosis. When SBP is elevated, both LV output impedance and intramyocardial wall tension increase, resulting in increased myocardial oxygen demand.


When SBP is elevated, both LV output impedance and intramyocardial wall tension increase, resulting in increased myocardial oxygen demand. The wide pulse pressure and systolic hypertension in older individuals are usually attributable to inappropriately high aortic impedance, which results from decreased aortic diameter or increased effective stiffness caused by aortic wall thickening and changes in wall composition. Aging is associ- ated with thinning and fragmentation of vascular elastin and increased collagen deposition, a degenerative process that causes increased arterial stiffness (reduction of elasticity) with an associated elevation in SBP and widening of the pulse Rosendorff et al Treatment of Hypertension in Patients With CAD 1379 Increased arterial stiffness elevates SBP by increasing pulse-wave velocity and altering wave reflection from the With each ejection of blood from the LV, a pressure (pulse) wave is generated and travels from the heart to the periphery at a pulse-wave velocity that depends on the elastic properties of the conduit arteries. The pulse wave is reflected at any point of discontinuity in the arterial tree and returns to the aorta and LV. The elastic properties and length of the conduit arteries determine the timing of the In younger people, the pulse-wave velocity is sufficiently slow ( 5 m/s) that the reflected wave reaches the aortic valve after closure, leading to a higher DBP and enhancing coronary perfusion by providing a boosting effect. In older people, particularly those who are hyper- tensive, pulse-wave velocity is greatly increased ( 20 m/s) because of central arterial stiffening. Thus, the reflective wave reaches the aortic valve before closure, leading to the higher SBP, pulse pressure, and afterload and a lower DBP. The increase in SBP increases cardiac metabolic require- ments and predisposes to the development of LV hypertro- phy and HF.


The increase in SBP increases cardiac metabolic require- ments and predisposes to the development of LV hypertro- phy and HF. Pulse pressure is closely related to SBP and is linked to CVD events, including MI and stroke. Aortic stiff- ness is an independent predictor of all-cause and cardiovas- cular mortality, fatal and nonfatal coronary events, and fatal stroke in patients with hypertension, type 2 diabetes mel- litus, and end-stage renal disease.73 1.2.3. Endothelial Dysfunction Endothelial dysfunction, characterized by an unfavorable balance between vasodilators, for example, nitric oxide and , and vasoconstrictors, for example, endo- thelin and angiotensin II, is an important contributor to BP elevation in people with vascular disease. The injured endothelium loses its vasodilator capacity and contributes to thrombosis and vascular occlusion. Release of chemotac- tic cytokines and adhesion molecules at the luminal surface of the injured endothelium promotes adhesion of circulat- ing mononuclear leukocytes to the vessel wall. This low- grade, self-perpetuating vascular inflammation underlies the atherosclerotic process. Inflammatory mediators activate medial smooth muscle cells, causing them to proliferate and migrate into the subintimal space. In the presence of dyslip- idemia, monocytes in the vessel wall incorporate oxidized low-density lipoprotein cholesterol and become lipid-laden macrophages, the core of the atherosclerotic plaque. In established lesions, resident macrophages secrete metal- loproteinases and cathepsins, destabilizing the fibrous cap of the plaque, which may result in plaque rupture and the release of tissue factor to cause thrombosis, coronary occlu- sion, and acute MI.


In established lesions, resident macrophages secrete metal- loproteinases and cathepsins, destabilizing the fibrous cap of the plaque, which may result in plaque rupture and the release of tissue factor to cause thrombosis, coronary occlu- sion, and acute MI. Endothelial dysfunction and decreased nitric oxide avail- ability related to mechanical and inflammatory injury of arter- ies are also associated with increased arterial stiffness and the development of isolated systolic hypertension.75 A decline in flow-mediated vasodilator capacity attributable to decreased endothelium-derived nitric oxide occurs in aging and subclini- cal vascular disease.76 Impaired endothelium-mediated vaso- dilation is responsible for the exaggerated exercise-induced increases in BP seen in these population groups.77 1.2.4. Oxidative Stress Oxidative stress is a critical feature of both hypertension and In vascular tissue, the principal effectors of oxidative injury are the NAD(P)H oxidases, which are acti- vated by mechanical forces (eg, hypertension), hormones (particularly angiotensin II), oxidized cholesterol, and cyto- kines. Several NAD(P)H oxidase isoforms expressed in endo- thelial and vascular smooth muscle cells are upregulated in the setting of atherosclerosis and arterial injury. Angiotensin II receptor dependent activation of NAD(P)H oxidase stim- ulates formation of oxidant superoxide anion (O2 ), which reacts with nitric oxide to form the powerful oxidant per- oxynitrite (ONOO ). The resultant reduction in nitric oxide bioactivity contributes to the vasoconstrictor response to angiotensin II and elevates BP. Angiotensin II induced activa- tion of NAD(P)H oxidase also stimulates oxidation of low- density lipoprotein cholesterol and increases the expression of monocyte chemoattractant protein-1 and vascular cell adhe- sion molecule-1, thus linking activation of the RAAS to the atherosclerotic process. 1.2.5. Humoral and Metabolic Factors Many of the mechanisms that initiate and maintain hyper- tension also damage target organs, including the coronary arteries and the myocardium.


Humoral and Metabolic Factors Many of the mechanisms that initiate and maintain hyper- tension also damage target organs, including the coronary arteries and the myocardium. Angiotensin II elevates BP and promotes target-organ damage, including atherosclerosis, by mechanisms that include direct effects on constriction and remodeling of resistance vessels, stimulation of aldosterone synthesis and release, enhancement of sympathetic outflow from the brain, and facilitation of catecholamine release from the adrenals and peripheral sympathetic nerve terminals.1 Aldosterone can mimic or potentiate the vasotoxic properties of angiotensin II and norepinephrine. Angiotensin II promotes cardiac and vascular smooth muscle cell hypertrophy directly via activation of the angiotensin II type 1 (AT1) receptor and indirectly by stimulating expression of a number of growth factors, cytokines, and adhesion molecules. AT1 receptor activation also contributes to endothelial damage and athero- genesis by inhibiting the mobilization of endothelial progeni- tor cells from the bone marrow, thus impairing endothelial regeneration and vascular repair processes.78 There is also a link between RAAS activation and fibrinolysis. Angiotensin II induces the formation of plasminogen activator inhibitor-1 via an AT1 receptor dependent effect on endothelial cells, whereas ACE downregulates tissue plasminogen activator production by degrading bradykinin, a potent stimulator of endothelial tissue plasminogen activator expression. ACE inhibitors and ARBs limit oxidative reactions in the vasculature by blocking the activation of NAD(P)H oxi- dase, supporting the concept that these RAAS blockers may have important vasoprotective effects beyond BP lowering.79 Furthermore, there is evidence of interaction between the RAAS and dyslipidemia: Hypercholesterolemia upregulates the RAAS, particularly vascularAT1 receptor density and func- tional responsiveness, and systemic angiotensin II peptide syn- whereas the RAAS stimulates the accumulation of low-density lipoprotein cholesterol in the arterial wall. These findings suggest that these antihypertensive drug classes may have clinically important vasoprotective effects beyond BP lowering.


These findings suggest that these antihypertensive drug classes may have clinically important vasoprotective effects beyond BP lowering. This hypothesis has yet to be supported by the results of randomized, controlled trials.82 Recent evidence suggests that a second angiotensin II receptor subtype (AT2), which is not expressed in the normal vasculature but appears to be induced in the setting of vascular inflammation/hypertension/atherosclerosis, may oppose the vasoconstrictor, antinatriuretic, and proinflammatory effects Because of the apparent vasoprotective effects of AT2 receptor activation, AT2 receptor agonists have been considered for the treatment of hypertension,84 but there is no evidence that they are effective in treating hypertension in humans. Calcium ions (Ca2+ ) are major intracellular mediators of vas- cular smooth muscle cell contraction and inotropic and chro- notropic functions of the heart. Ca2+ enters vascular smooth muscle cells, cardiomyocytes, and pacemaker cells via volt- age-dependent L- and T-type calcium channels. In vascular smooth muscle, the voltage-gated L-type (long-acting, slowly activating) channel allows entry of sufficient Ca2+ for the ini- tiation of contraction by calcium-induced intracellular Ca2+ release from the sarcoplasmic reticulum. Increased intracel- also has atherosclerosis-promoting effects. The dihydropyridine CCBs bind to the 1 subunit of the L-type channel and are highly selective for arterial/arterio- lar tissues, including the coronary arteries, where they are vasodilators. The nondihydropyridine CCBs, including the phenylalkylamines (verapamil-like) and benzothiazepines (diltiazem-like), bind to different sites on the 1 subunit and are less selective for vascular tissue; they have nega- tive chronotropic and dromotropic effects on sinoatrial and atrioventricular nodal conducting tissue and negative ino- tropic effects on cardiomyocytes.


The nondihydropyridine CCBs, including the phenylalkylamines (verapamil-like) and benzothiazepines (diltiazem-like), bind to different sites on the 1 subunit and are less selective for vascular tissue; they have nega- tive chronotropic and dromotropic effects on sinoatrial and atrioventricular nodal conducting tissue and negative ino- tropic effects on cardiomyocytes. The nondihydropyridine CCBs have greater effects on the atrioventricular node than on the sinoatrial node and may predispose to high-degree atrioventricular block in patients with preexisting atrioven- tricular nodal disease or when given with other agents, for example, -blockers, that depress the atrioventricular node. Both CCB subclasses are indicated for the treatment of hypertension and angina pectoris. The antianginal effects of CCBs result from afterload reduction, that is, their ability to decrease SBP, as well as coronary vasodilation and, in the case of nondihydropyridine CCBs, heart rate slowing. CCBs are particularly effective in treating angina caused by coronary spasm, for example, the Prinzmetal variant or 2. Prevention of Cardiovascular Events in Patients With Hypertension and CAD 2.1. Antihypertensive Drugs for the Secondary Prevention of Cardiovascular Events in Patients With CAD Meta-analyses of antihypertensive trials have demonstrated that BP lowering is more important than the particular drug class used in the primary prevention of the complications of hypertension, including IHD. Combination antihypertensive drug therapy is typically needed to achieve and to sustain effective long-term BP control. Thus, there is no evidence to support initiating therapy with any one antihypertensive drug class over another for the primary prevention of IHD. In con- trast, for secondary protection in individuals with underlying comorbid illnesses such as IHD, CKD, or recurrent stroke, not all drug classes have been proven to confer optimal or even the same level of benefit.


In con- trast, for secondary protection in individuals with underlying comorbid illnesses such as IHD, CKD, or recurrent stroke, not all drug classes have been proven to confer optimal or even the same level of benefit. Whether there are class effects for antihypertensive drugs and whether each drug should be considered individually on the basis of trial results are not clearly known. It is reasonable to assume that there are class effects for thiazide and thiazide- type diuretics, ACE inhibitors, and ARBs, which have a high degree of homogeneity in both their mechanisms of action and side effects.13,86,87 There are major pharmacological dif- ferences between drugs within more heterogeneous classes of agents such as the -blockers and CCBs.88,89 Finally, the most recent trials suggest that combining ACE inhibitors and ARBs is not beneficial for the secondary prevention of cardiovas- whereas combinations of renin-angiotensin blocking agents with thiazide diuretics or with CCBs show important clinical benefits.92 2.1.1.


It is reasonable to assume that there are class effects for thiazide and thiazide- type diuretics, ACE inhibitors, and ARBs, which have a high degree of homogeneity in both their mechanisms of action and side effects.13,86,87 There are major pharmacological dif- ferences between drugs within more heterogeneous classes of agents such as the -blockers and CCBs.88,89 Finally, the most recent trials suggest that combining ACE inhibitors and ARBs is not beneficial for the secondary prevention of cardiovas- whereas combinations of renin-angiotensin blocking agents with thiazide diuretics or with CCBs show important clinical benefits.92 2.1.1. Thiazide and Thiazide-Type Diuretics Thiazide diuretics and the thiazide-type diuretics chlorthali- done and indapamide are highly effective in reducing BP and preventing cerebrovascular events, as demonstrated most con- vincingly in early studies such as the Veterans Administration the Medical Research Council (MRC) Trial,94 the Systolic Hypertension in the Elderly Program (SHEP),95 and the Hypertension in the Very Elderly Trial (HYVET).15 The benefit of chlorthalidone-based therapy in hypertension treatment is evident from the Antihypertensive and Lipid- Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Since the publication of the results of ALLHAT, there have been concerns about whether thiazide-induced hyper- glycemia and diabetes mellitus contribute to long-term IHD risk not measured during the study interval,97 but this does not seem to be the case.98-100 -Blockers make up a heterogeneous class of antihyperten- sive drugs with differing effects on resistance vessels and on cardiac conduction and contractility. -Blocker administration remains the standard of care in patients with angina pectoris, those who have had an MI, and those who have LV dysfunc- tion with or without symptoms of HF unless contraindicated. The -blockers carvedilol, metoprolol, and bisoprolol have been shown to improve outcomes in patients with HF.1 2.1.3.


The -blockers carvedilol, metoprolol, and bisoprolol have been shown to improve outcomes in patients with HF.1 2.1.3. ACE Inhibitors TheACE inhibitors are effective in reducing initial IHD events and are recommended for consideration in all patients after MI. They are proven to prevent and improve both HF101,102 and the progression of CKD.103 When combined with thiazide diuretics, ACE inhibitors reduce the incidence of recurrent Major trials have addressed the use of ACE inhibi- tors in patients with IHD but without HF or known significant LV systolic impairment. In the HOPE study,16 9297 high-risk patients, of whom 80% had a history of CAD, were assigned to receive either Rosendorff et al Treatment of Hypertension in Patients With CAD 1381 ramipril (10 mg once nightly) or placebo and followed up for a mean of 5.0 years. Treatment with ramipril was associ- ated with a 22% reduction in the composite end point of car- diovascular death, MI, and stroke (P<0.001) and comparably significant reductions in each of the individual components. There were also significant reductions in the rates of revascu- larization, cardiac arrest, HF, worsening angina, and all-cause mortality with ramipril therapy. The mean reduction in the clinic BP with active treatment was 3/2 mmHg. These car- diovascular benefits were initially thought to be independent of BP, but an interesting but very small HOPE substudy105 revealed a more marked reduction in 24-hour ambulatory BP with ramipril not observed in the main trial, which reported only the clinic BPs. In EUROPA, 12218 patients were randomized to the ACE inhibitor perindopril or placebo.18 Although just 27% of patients were classified as hypertensive, the definition of hypertension was based on a clinic BP >160/95 mmHg or antihypertensive therapy at baseline. The mean follow-up in EUROPA was 4.2 years.


In EUROPA, 12218 patients were randomized to the ACE inhibitor perindopril or placebo.18 Although just 27% of patients were classified as hypertensive, the definition of hypertension was based on a clinic BP >160/95 mmHg or antihypertensive therapy at baseline. The mean follow-up in EUROPA was 4.2 years. Treatment with perindopril (target dose, 8 mg daily) was associated with a 20% relative risk reduction in the composite end point of cardiovascular death, MI, or cardiac arrest (P<0.003). The benefit of active treat- ment with perindopril was similar for patients with or without hypertension as the investigators defined it. The mean reduc- tion in BP in the clinic setting was 5/2 mmHg. At baseline, EUROPA patients were at lower cardiovascular risk than HOPE patients: One third were <55 years of age; fewer had diabetes mellitus (12% versus 39%); and proportionately more EUROPA patients took antiplatelet (92% versus 76%) and lipid-lowering (58% versus 29%) drugs. Patients in the Prevention of Events With Angiotensin Converting Enzyme Inhibition (PEACE) trial106 had stable CAD and normal or slightly reduced LV function and were randomized to trandolapril (target dose, 4 mg) or placebo. Median follow-up was 4.8 years. No difference between the groups was found in the incidence of the primary compos- ite end point of cardiovascular death, MI, or coronary artery revascularization. Forty-six percent of patients were hyper- tensive, and treatment with trandolapril was associated with a mean reduction in BP of 4.4/3.6 mmHg. The annualized rate of all-cause mortality in PEACE was only 1.6%, a rate similar to that of an age- and sex-matched cohort without IHD. There was a relatively high use of revascularization before random- ization in the PEACE trial, which may have contributed to the low event rate.


There was a relatively high use of revascularization before random- ization in the PEACE trial, which may have contributed to the low event rate. The investigators concluded that ACE inhibitors might not be necessary as routine therapy in low-risk IHD patients with preserved LV function, especially those who have received intensive treatment with revascularization and lipid-lower- ing agents. Thus, 2 large studies in high-cardiovascular-risk patients (HOPE and EUROPA) showed cardiovascular protec- tive effects by ACE inhibitors, and 1 study in low-cardiovas- cular-risk patients (PEACE) did not. The Ongoing Telmisartan Alone and In Combination with Ramipril Global Endpoint Trial (ONTARGET)90 trial random- ized 25620 patients, of whom 74% had a history of CAD, to the ACE inhibitor ramipril (10 mg/d), the ARB telmisar- tan (80 mg/d), or the combination of these 2 drugs. After a median follow-up of 4.7 years, there was no difference in the primary outcome of cardiovascular death, nonfatal MI, non- fatal stroke, and hospitalization for HF among the 3 groups. In the combination treatment group, there was an increased risk of hypotensive symptoms, syncope, and renal dysfunction compared with those in the ramipril group. The investigators concluded that ramipril and telmisartan had similar benefits but that the combination of the ACE inhibitor and ARB in this high-cardiovascular-risk group was associated with more side effects and no increase in benefit. 2.1.4. Angiotensin Receptor Blockers Several ARBs have been shown to reduce the incidence or severity of IHD events, the progression of renal disease in type 2 diabetes mellitus, and cerebrovascular events. ARBs are often considered to be an alternative therapy in individu- als with cardiovascular disease who are intolerant of ACE inhibitors.


ARBs are often considered to be an alternative therapy in individu- als with cardiovascular disease who are intolerant of ACE inhibitors. In the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) study, protection against a composite of cardiovascular events that included MI and HF was similar to that observed for the CCB amlodipine.107 However, there were important differences in BP control in the early stages of the VALUE trial (a significant BP difference in favor of amlodipine) that may have confounded outcomes for MI and Beneficial cardiovascular outcomes were not shown in the Optimal Trial in Myocardial Infarction With the Angiotensin II Antagonist Losartan (OPTIMAAL).109 The lack of ben- efit may have been attributable to inadequate doses of losar- tan. In the Valsartan in Acute Myocardial Infarction Trial (VALIANT), the ARB valsartan had effects similar to those of the ACE inhibitor captopril in reducing cardiovascular event The combination of theARB with theACE inhib- itor yielded an increase in adverse events with no incremental benefit for cardiovascular events. In the Telmisartan Randomised Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease 5296 high-risk patients, of whom 75% had CAD, were randomized to telmisartan (80 mg daily) or placebo for a median duration of 4.7 years. The mean BP in the telmisartan group was 4.0/2.2 mmHg lower than that in patients randomized to placebo. The primary outcome of cardiovascular death, nonfatal MI, nonfatal stroke, and hospi- talization for HF occurred in 15.7% of the telmisartan group and 17.0% of the placebo group (P=0.216). The composite of cardiovascular death, nonfatal MI, and stroke occurred in 13% of patients on telmisartan versus 14.8% of the placebo group (P=0.048), and fewer patients in the telmisartan group had a cardiovascular hospitalization (30.3% versus 33%; P=0.025). The tolerability of telmisartan was similar to that of placebo.