ischemic heart disease chapter 17

1. Ischemic Heart DiseaseChapter 17

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3. DCA: directional coronary atherectomy ECG: electrocardiogram EDRF: endothelium-derived relaxing factor ETT: exercise tolerance (stress) testing GMP: guanosine monophosphate HDL: high-density lipoprotein HERS: Heart Estrogen/Progestin Replacement Study IHD: ischemic heart disease I Na: late sodium current ISDN: isosorbide dinitrate ISMN: isosorbide mononitrate 3 Abbreviations

4. Abbreviations LAD: left anterior descending LDL: low-density lipoprotein LV: left ventricle MI: myocardial infarction MVO2: myocardial oxygen demand PCI: primary coronary intervention PTCA: percutaneous transluminal angioplasty R1: resistance 1-large epicardial or surface vessels R2: resistance 2-intramyocardial arteries and arterioles 4

5. Key Concepts Ischemic heart disease (IHD): caused by coronary atherosclerotic plaque formation which leads to imbalance between O2 supply & demand results in myocardial ischemia Chest pain: cardinal symptom of myocardial ischemia caused by coronary artery disease (CAD) Risk factor identification/modification important interventions for patients with known/suspected IHD 5

6. Major risk factors that can be altered dyslipidemia high total & low-density lipoprotein cholesterol low high-density lipoprotein cholesterol high triglycerides smoking glycemic control in DM HTN therapeutic lifestyle changes exercise, weight reduction, reduced dietary cholesterol reduction in inflammation may play an important role 6 Key Concepts

7. Key Concepts Most CAD patients should receive antiplatelet therapy Manage chronic stable angina patients initially with �-blockers for symptomatic control at least as well as nitrates or CCBs decrease risk of recurrent MI, CAD mortality Nitroglycerin, other nitrate products useful for angina prophylaxis when patients undertake activities known to provoke angina When angina occurs on a regular, routine basis institute chronic prophylactic therapy 7

8. CCBs: effective monotherapy generally used with �-blockers or as monotherapy for patients intolerant to �-blockers most patients with moderate to severe angina require 2 drugs to control symptoms ranolazine: 2nd line drug used with �-blockers & CCBs 8 Key Concepts

9. Key Concepts Pharmacologic management as effective as revascularization if 1 or 2 vessels involved no differences in survival recurrent MI other measures of effectiveness Multivessel involvement best managed with revascularization left main coronary artery disease left main equivalent disease 2- to 4-vessel involvement with significant left ventricular dysfunction 9

10. Key Concepts Revascularization percutaneous transluminal coronary angioplasty coronary artery bypass graft (CABG) certain patients (e.g. diabetics) should have CABG Percutaneous transluminal coronary angioplasty & CABG produce similar results 10

11. BP lipid profile drug therapy hyperlipidemia symptom & activity assessment smoking cessation antiplatelet therapy �-blocker therapy for prior myocardial infarction ACE inhibitor therapy diabetes screening 11 Key Concepts

12. Ischemic Heart Disease Caused by epicardial vessel atherosclerosis which leads to coronary heart disease Presentation: acute coronary syndrome chronic stable exertional angina pectoris ischemia without clinical symptoms heart failure, arrhythmias cerebrovascular disease peripheral vascular disease 12

13. Epidemiology ~79 million American adults: > 1 type of cardiovascular disease (CVD) ~2,400 Americans die of CVD each day average of 1 death every 33 seconds In 2004, CHD was responsible for 52% of CVD deaths Common initial presentation: women: angina men: myocardial infarction 13

14. Criteria for Determination of the Specific Activity Scale Functional Class 14

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16. Angina Classified by symptom severity, disability, specific activity scale Number of vessels obstructed important determinate of outcome Risk factors for increased mortality: heart failure smoking left main or left main equivalent CAD diabetes prior MI 16

17. Grading of Angina Pectoris by the Canadian Cardiovascular Society Classification System 17

18. Etiology/Pathophysiology Coronary atherosclerotic plaque formation leads to imbalance between O2 supply & demand ? myocardial ischemia Ischemia: lack of O2, decreased or no blood flow in myocardium Anoxia: absence of O2 to myocardium 18

19. Etiology/Pathophysiology Determinants of myocardial oxygen demand (MVO2) HR contractility intramyocardial wall tension during systole (most important) Determinants of ischemia: resistance in vessels delivering blood to myocardium MVO2 19

20. Etiology/Pathophysiology Coronary blood flow inversely related to arteriolar resistance directly related to coronary driving pressure Extent of functional obstruction important limitation of coronary blood flow severe stenosis (> 70%) ischemia & symptoms at rest

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22. Etiology/Pathophysiology Changes in O2 balance lead to rapid changes in coronary blood flow Mediators that affect O2 balance: adenosine other nucleotides nitric oxide prostaglandins CO2 H+

23. Etiology/Pathophysiology Extrinsic factors alterations in intramyocardial wall tension throughout the cardiac cycle phasic systolic vascular bed compression factors that favor reduction in blood flow Intrinsic factors myogenic control Bayliss effect neural components parasympathetic nervous system, sympathetic nervoussystem, coronary reflexes

24. Etiology/Pathophysiology Factors limiting coronary perfusion: coronary reserve diminished at ~85% obstruction critical stenosis occurs when obstructing lesion encroaches on the luminal diameter & exceeds 70%

25. 25 Short-Term Risk of Death or Nonfatal Myocardial Infarction in Patients with Unstable Angina

26. Clinical Presentation of Angina Many ischemia episodes are silent (no symptoms) Patients often have reproducible pattern, pain, other symptoms Increased frequency, severity, duration, symptoms at rest suggests unstable angina 26

27. Clinical Presentation of Angina Symptoms sensation of pressure/burning over or near sternum; often but not always radiating left jaw, shoulder, arm chest tightness, shortness of breath visceral pain: lasts 0.5 to 30 min precipitating factors: exercise, cold environment, walking after a meal, emotional upset, fright, anger, coitus relief with rest, nitroglycerin 27

28. Clinical Presentation of Angina Signs abnormal precordial systolic bulge abnormal heart sounds Typically no abnormal laboratory tests Likely to have abnormal tests for IHD risk factors History of chest pain 28

29. Differential Diagnosis of Episodic Chest Pain Resembling Angina Pectoris 29

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31. 31 Cardiac Findings in CAD Patients

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33. Diagnostic Tests Electrocardiogram (ECG) normal in � of patients with angina not experiencing an acute attack ST-T wave changes depression T-wave inversion ST-segment elevation significant ischemia ST-segment depression > 2 mm exertional hypotension reduced exercise tolerance 33

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35. Diagnostic Tests Exercise Tolerance Testing (ETT) recommended for patients with intermediate pretest probability of CAD based on age, gender, symptoms insensitive for predicting coronary artery anatomy but correlates well with outcome Echocardiography useful if physical examination suggests valvular, pericardial disease, ventricular dysfunction 35

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37. Diagnostic Tests Cardiac imaging radionucleotide angiocardiography technetium pyrophosphate scans positron emission tomography ultrarapid computerized tomography spiral CT ultrafast CT electron-beam CT Cardiac catheterization & angiography 37

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41. IHD Treatment Short term goals: reduce/prevent angina symptoms that limit exercise capability & impair quality of life (QOL) Long-term goals: prevent CHD events MI arrhythmias heart failure extend the patient�s life 41

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43. IHD Treatment Risk factor identification/modification risk factors play a major role in determining occurrence & severity of IHD risk factors are additive classified as alterable or unalterable 43

44. IHD Treatment Unalterable risk factors: gender age family history environmental influences climate, air pollution, trace metals in drinking water diabetes mellitus 44

45. Alterable risk factors: smoking HTN hyperlipidemia obesity, sedentary lifestyle hyperuricemia psychosocial factors (stress, type A behavior) medications progestins corticosteroids cyclosporine 45 IHD Treatment

46. The American College of Cardiology and American Heart Association Evidence Grading System 46

47. Stable Exertional Angina Pectoris ASA (Class I, Level A) �-blockers with prior MI (Class I, Level A) ACE inhibitors for patients with CAD & diabetes or LV systolic dysfunction (Class I, Level A) LDL-lowering therapy with CAD & LDL > 130 mg/dL (Class I, Level A) target LDL < 100 mg/dL < 70 mg/dL in patients with CHD & multiple risk factors Sublingual nitroglycerin for immediate angina relief (Class I, Level B) 47

48. Stable Exertional Angina Pectoris Calcium antagonists or long-acting nitrates for symptom reduction when �-blockers contraindicated (Class I, Level B) Calcium antagonists or long-acting nitrates in combination with �-blockers when initial �-blocker treatment is inadequate (Class I, Level C) Calcium antagonists or long-acting nitrates as substitutes for �-blockers if initial �-blocker treatment leads to intolerable side effects (Class I, Level A) 48

49. Stable Exertional Angina Pectoris May substitute clopidogrel when ASA contraindicated (Class IIa, Level B) Use of long-acting nondihydropyridine calcium antagonists instead of �-blockers as initial therapy (Class IIa, Level B) Therapies to avoid: dipyridamole (Class III, Level B) chelation therapy (Class III, Level B) 49

50. Effect of Drug Therapy on Myocardial O2 Demand 50

51. Stable Exertional Angina Pectoris �-blocker place in therapy: effective in chronic exertional angina as monotherapy and in combo with nitrates and/or CCBs 1st line in chronic angina that requires daily maintenance therapy ideal candidates: physical activity figures prominently in anginal attacks coexistent hypertension history of supraventricular arrhythmias or post-MI angina anxiety associated with angina 51

52. Stable Exertional Angina Pectoris �-blockers symptom control reduce risk of recurrent MI, CAD mortality may be used for chronic prophylaxis in patients with > 1 angina episodes/day smokers have reduced anti-anginal efficacy some have reduced efficacy based on lipid solubility propranolol: lipid soluble, inducible metabolism 52

53. Stable Exertional Angina Pectoris �-blockers overall effect of �-blockers in patients with effort-induced angina ? reduction in O2 demand do not improve O2 supply can blunt reflex tachycardia from nitrate therapy may decrease exercise capacity in healthy individuals or those with HTN may improve exercise tolerance in angina patients 53

54. Stable Exertional Angina Pectoris �-blockers dosing based on t� disparity between t� & duration of action for several BBs renal/hepatic dysfunction affect disposition route of elimination not major consideration in drug selection 54

55. Stable Exertional Angina Pectoris �-blocker adverse effects abrupt withdrawal associated with increased severity & number of pain episodes & myocardial infarction pharmacologic effects CNS effects fatigue malaise depression 55

56. chewable oral transdermal ointments spray IV 56 Stable Exertional Angina Pectoris

57. Stable Exertional Angina Pectoris Nitrate therapy for acute attacks sublingual buccal spray products Symptom prophylaxis when undertaking activities that precipitate attacks oral or transdermal products 0.3 to 0.4 mg SL ~5 min prior to activity Chronic prophylaxis with long-acting forms tolerance: limiting factor 57

58. Stable Exertional Angina Pectoris Nitrate therapy reduces MVO2 2? to venodilation & arterial-arteriolar dilation ? reduction in wall stress from reduced ventricular volume & pressure systemic venodilation increases flow to deep myocardial tissue dilation of large & small intramural coronary arteries, collateral dilation, coronary artery stenosis dilation, abolition of normal tone in narrowed vessels, relief of spasms 58

59. Stable Exertional Angina Pectoris Nitrate therapy large 1st-pass effect short t� (except isosorbide mononitrate) see Nitrate Products chart on slide 61 large volume of distribution high clearance rates large interindividual variation in plasma/blood concentrations saturable metabolism accumulation of metabolites with multiple doses drug adsorption to PVC tubing, syringes 59

60. Stable Exertional Angina Pectoris Nitrate therapy adverse effects extension of pharmacologic effects postural hypotension with CNS symptoms, headaches, flushing 2? to vasodilation occasional nausea from smooth muscle relaxation reflex tachycardia, but bradycardia has been reported rash with all products (particularly with patches) production of methemoglobinemia with high doses for extended periods measurable ethanol & propylene glycol concentrations with IV nitroglycerin tolerance 60

61. Nitrate Products 61

62. Stable Exertional Angina Pectoris Calcium channel blockers (CCBs) effective monotherapy (usually used if patients are intolerant of �-blockers) generally used in combination with �-blockers improve coronary blood flow through coronary artery vasodilation, decrease MVO2 provide better skeletal muscle oxygenation than �-blockers ? decrease fatigue, improve exercise tolerance CCBs have similar efficacy differences in electrophysiology, peripheral/central hemodynamic effects, ADR profiles useful in selecting appropriate agent 62

63. Stable Exertional Angina Pectoris Calcium channel blockers (CCBs) ideal candidates contraindications/intolerance to �-blockers coeixting conduction system disease (except verapamil, diltiazem) Prinzmetal angina peripheral vascular disease severe ventricular dysfunction (amlodipine drug of choice) concurrent HTN 63

64. Stable Exertional Angina Pectoris Calcium channel blockers (CCBs) vasodilation of systemic arterioles & coronary arteries reduction of arterial pressure and coronary vascular resistance depression of myocardial contractility & conduction velocity of the SA/AV nodes MVO2 reduction due to reduced wall tension 2? to reduced arterial pressure may improve coronary blood flow through areas of fixed coronary obstruction inhibits coronary artery vasomotion/vasospasm non-dihydropyridine products affect AV conduction and contractility 64

65. Stable Exertional Angina Pectoris Calcium channel blockers (CCBs) large, variable, 1st-pass metabolism ~20 to 50% bioavailability for diltiazem, nicardipine, nifedipine, verapamil, felodipine, isradipine amlodipine bioavailability ~60 to 80% most CCBs eliminated via CYP 3A4 & other CYP isoenzymes 65

66. Stable Exertional Angina Pectoris Ranolazine reduces Ca2+ overload in ischemic myocytes through selective inhibition of late Na+ current (INa) does not affect HR, inotropic state, hemodynamic state or increase coronary blood flow indicated for chronic angina treatment prolongs QT interval reserved for patients who have not achieved adequate response with other antianginal agents 66

67. Ranolazine dose: 500 mg BID then 1000 mg BID contraindications preexisting QT interval prolongation hepatic impairment drug interactions other QT interval-prolonging medications cytochrome P450 3A inhibitors decrease ranolazine clearance 67 Stable Exertional Angina Pectoris

68. Clinical Controversy MERLIN-TIMI 36 Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes Randomized, double-blind, controlled trial (n=6560) 2 groups ranolazine 1000 mg BID placebo 68

69. MERLIN-TIMI 36 results NSTEMI angina symptom relief 6.2% HbA1c reduction at 4 months: ranolazine group 5.9% HbA1c reduction at 4 months: placebo 0.30 versus 0.04 (p<0.001) � clinical significance? no significant reduction in composite 1� outcome at (median follow-up 348 days) CV death MI, recurrent ischemia 69 Clinical Controversy

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72. Stable Exertional Angina Pectoris Nonpharmacologic therapy revascularization coronary artery bypass grafting percutaneous transluminal coronary angioplasty 72

73. 73 Recommended Mode of Coronary Revascularization��

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75. Stable Exertional Angina Pectoris Revascularization based on extent of coronary disease (# of vessels, location/amount of stenosis) & ventricular function complications: coronary artery spasm, intraluminal thrombus combination therapy with acetylsalicylic acid, unfractionated heparin, or low-molecular-weight heparin, glycoprotein IIb/IIIa receptor antagonists & stents have reduced occurrence of reocclusion & late restenosis 75

76. Stable Exertional Angina Pectoris Coronary artery bypass grafting (CABG) reduces symptomatic angina not controlled by medical management or PCI improves patient lifestyle reduces CAD mortality reduces need for nitrates, �-blockers 76

77. Stable Exertional Angina Pectoris Percutaneous transluminal coronary angioplasty (PTCA) reduced stenosis due to compression, redistribution of plaque embolization of plaque contents aneurysm formation disruption of plaque & arterial wall patients usually heparinized during PTCA to prevent immediate thrombus formation at site of arterial injury anticoagulation up to 24 hrs 77

78. Stable Exertional Angina Pectoris Percutaneous transluminal coronary angioplasty (PTCA) prevention of restenosis: combination therapy with acetylsalicylic acid, heparin, GP IIa/IIIa receptor antagonists bivalirudin drug-eluting & bare metal stents 78

79. Stable Exertional Angina Pectoris PTCA vs CABG low-risk patients have greater alleviation of symptoms with PTCA moderate-risk patients had equal mortality & MI rates with PTCA or CABG high-risk patients showed improved survival with CABG than medical therapy 79

80. Stable Exertional Angina Pectoris Drug-eluting stents sirolimus (Cypher�) paclitaxel (Taxus�) zotarolimus (Endeavor�) target revascularization needed less often than bare stents combination antiplatelet therapy (ASA + clopidogrel) for > 1 yr following implantation 80

81. Drug-eluting stents Antiplatelet therapy often discontinued in surgical patients with drug-eluting stents risk factor for late stent thrombosis Medline search for late & very late stent thrombosis cases Jan 2001 to July 2008 When patients stopped antiplatelet agents simultaneously, median time to event: 7 days If the thienopyridine was stopped & ASA continued, median time to event: 122 days 81

82. Variant Angina Pectoris Prinzmetal angina associated with ST-segment elevation commonly resolves without progression to MI usually younger patients 82

83. Variant Angina Pectoris Causes imbalance between endothelium-produced vasodilator factors (prostacyclin, nitric oxide) & vasoconstrictor factors (endothelin, angiotensin II) imbalance of autonomic control characterized by parasympathetic dominance of inflammation adrenoreceptor polymorphisms may predispose patients to developing vasospasm 83

84. Variant Angina Pectoris Precipitating factors hyperventilation exercise exposure to cold May have no apparent precipitating cause 84

85. Coronary Artery Spasm Diagnosis ST-segment elevation during transient chest discomfort (usually at rest) that resolves when chest discomfort diminishes in patients with normal or non-obstructive lesions In absence of ST-segment elevation, may use provocative tests to precipitate coronary artery spasm ergonovine, acetylcholine, methacholine withdraw nitrates & CCB prior to testing 85

86. Coronary Artery Spasm Treatment optimization of therapy includes dose titration treat all patients for acute attacks maintain prophylactic treatment 6 to 12 months following initial episode eliminate aggravating factors alcohol cocaine cigarette smoking 86

87. Coronary Artery Spasm Treatment nitrates for acute attacks CCBs nifedipine, verapamil, diltiazem equally effective single agents for initial treatment dose titration needed combination therapy with nifedipine-diltiazem or nifedipine-verapamil useful for patients unresponsive to single-drug regimens �-blockers have little or no role 87

88. Silent Ischemia Associated with ST-segment elevation, depression Frequently occurs without antecedent HR, BP changes ischemia from reduction in O2 supply 2 classes Class I: patients do not experience angina Class II: patients have both asymptomatic & symptomatic ischemia Associated with reduced survival, increased need for PTCA/CABG, increased risk of acute MI 88

89. Silent Ischemia Causes increased physical activity sympathetic nervous system activation ? cortisol secretion ? coronary artery tone enhanced platelet aggregation due to endothelial dysfunction leading to intermittent coronary obstruction 89

90. Silent Ischemia Diagnosis: ambulatory ECG Initial management modify IHD risk factors HTN hypercholesterolemia smoking Treatment goal reduce number of ischemic episodes (symptomatic & asymptomatic), regardless of direction of ST-segment shift 90

91. Silent Ischemia Pharmacologic treatment �-blockers most useful for post-MI patients or those with high level of sympathetic nervous system activity CCBs alone or in combination effective in reducing symptomatic & asymptomatic ischemia do not interrupt diurnal surge in ischemia less effective than �-blockers combination �-blockers & CCBs: better response than CCBs & nitrates or CCB monotherapy 91

92. Therapeutic Outcomes Angina symptom improvement Improved cardiac performance Risk factor reduction Increased exercise capacity May use coronary angiography to assess extent of stenosis or restenosis after angioplasty or CABG 92

93. Clinical Controversy Many long-term trials compare �-blockade vs CCBs to determine superior survival benefit �-blockers recommended 1st line prophylactic therapy for symptomatic angina patients requiring daily pharmacologic therapy effective in post-MI patients favorable adverse effect profile Stable CAD: medical management produces outcomes similar to revascularization may impact future use of healthcare resources 93

94. Recent developments in understanding organic nitrates bioactivation raise concern over endothelial dysfunction induced by long-term nitrate administration Nitrate products activated via different mechanisms impacts long-term effectiveness of individual drugs 94 Clinical Controversy

95. 95 American College of Cardiology, American Heart Association, and Physician Consortium for Performance Improvement Chronic Stable Coronary Artery Disease Core Physician Performance Measurement Seta

96. 96 American College of Cardiology, American Heart Association, and Physician Consortium for Performance Improvement Chronic Stable Coronary Artery Disease Core Physician Performance Measurement Seta

97. 97 American College of Cardiology, American Heart Association, and Physician Consortium for Performance Improvement Chronic Stable Coronary Artery Disease Core Physician Performance Measurement Seta

98. Table Footnotes aRefers to all patients diagnosed with CAD bMedical reasons for not prescribing antiplatelet therapy (aspirin, clopidogrel, or combination of aspirin and dipyridamole): active bleeding in the previous 6 months with required hospitalization and/or transfusion(s), patient on other antiplately therapy, etc. Medical reasons for not prescribing a statin: clinical judgement, documented LCL-C < 130 mg/dL, etc. Medical reasons for not prescribing a �-blocker: bradycardia (defined as heart rate < 50 beats/min without �-blocker therapy), history of class IV (congestive) heart failure, history of second- or third-degree atrioventricular block without permanent pacemaker, etc. Medical reasons for not prescribing ACE inhibitor (ACEI): allergy, angioedema caused by ACEI, anuric rental failure caused by ACEI, pregnancy, moderate or severe aortic stenosis, etc. cPatient reasons for not prescribing antiplatelet therapy, statin, -blocker, or ACEI: economic, social, and/or religious, etc. dAntiplatelet therapy may include aspirin, clopidogrel, or combination of aspirin and dipyridamole. eNot indicated for a statin refers to LCL-C < 100 mg/dL. fTest measure. gScreening for diabetes is usually done by fasting blood glucose or 2-hour glucose tolerance testing. Clinical recommendations indicate screening should be considered at 3-year intervals. 98

99. Acknowledgements Prepared By: Amy Pai, Pharm.D. Series Editor: April Casselman, Pharm.D. Editor-in-Chief: Robert L. Talbert, Pharm.D., FCCP, BCPS, FAHA Chapter Author/Section Editor: Robert L. Talbert, Pharm.D., FCCP, BCPS, FAHA 99