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GUIDELINES FOR THE MANAGEMENT OF CHRONIC STABLE ANGINA American College of Cardiology, Puerto Rico Chapter, February 6, 2007 GAP The Goals of Therapy in CAD To improve quality of life (symptoms) To reduce mortality To reduce morbidity To reduce progression of disease and induce regression. Treatment of Chronic Stable Angina Medical Revascularization PCI ACBG MEDICAL THERAPY ANTIPLATELETS BETA BLOCKERS NITRATES CALCIUM ANTAGONIST ACEI STATINS NEW THERAPIES ANTIPLATELET AGENTS ASA – Physicians’ Health Study – Swedish Angina Pectoris Trial TICLOPIDINE CLOPIDOGREL – CAPRI – CURE Receptor GP IIb-IIIa: The Final Common Pathway to Platelet Aggregation High-dose heparin stimulates PAF which activates platelets • GP IIb-IIIa inhibitors displace fibrinogen in existing thrombi to disaggregate thrombus and prevent further platelet crosslinking and thrombosis • GP IIb-IIIa inhibitors prevent platelet activation by blocking GP IIb-IIa (outsidein signaling) White HD. Am J Cardiol 1997; 80:2B-10B. Schafer A. J Clin Invest 1986; 78:73-79. DeJong MJ, et al. Critical Care Nursing Clin of N Am 1999; 11:355-371. Moser M, et al. J Cardiovasc Pharmacol 2003;41:586-592. Phillips DR, Scarborough RM. Am J Cardiol 1997;80(4A):11B-20B. PHYSICIANS' HEALTH STUDY A randomized, double-blind, placebo controlled trial designed to test the effects of low-dose aspirin and beta-carotene in the primary prevention of CVD and cancer among 22,071 US male physicians, aged 40 to 84 at baseline in 1982. Baseline blood specimens were collected and frozen for later analyses from 14,916 participants. Using a 2x2 factorial design: • 325 mg of aspirin (Bufferin, supplied by Bristol-Myers Products on alternate days) • 50 mg of beta-carotene (Lurotin, supplied by BASF AG on alternate days) PHYSICIANS' HEALTH STUDY Primary Endpoints • Total cancer • Prostate cancer • Cardiovascular disease • Eye disease Cataract Macular degeneration PHYSICIANS' HEALTH STUDY The trial's Data and Safety Monitoring Board stopped the aspirin arm of the PHS several years ahead of schedule because it was clear that aspirin had a significant effect on the risk of a first myocardial infarction. As reported in the July 20, 1989 New England Journal of Medicine, aspirin reduced the risk of first myocardial infarction by 44% (P less than 0.00001). There were too few strokes or deaths upon which to base sound clinical judgment regarding aspirin and stroke or mortality Pharmacotherapy for Chronic Stable Angina (class I) 1. Aspirin in the absence of contraindications A 2. Beta-blockers as initial therapy in the absence of contraindications in patients with prior myocardial infarction or without prior myocardial infarction A,B 3. ACE inhibitor in all patients with CAD who also have diabetes and/or LV systolic dysfunction A 4. LDL-lowering therapy in patients with documented or suspected CAD and LDL cholesterol >130 mg/dl, with a target LDL of <100 mg/dl A 5. Sublingual nitroglycerin or nitroglycerin spray for the immediate relief of angina B 6. Calcium antagonists † or long-acting nitrates as initial therapy for reduction of symptoms when beta blockers are contraindicated B 7. Calcium antagonists † or long-acting nitrates in combination with beta blockers when initial treatment with beta blockers is not successful B 8. Calcium antagonists † and long-acting nitrates as a substitute for beta blockers if initial treatment with beta blockers leads to unacceptable side effects Pharmacotherapy for Chronic Stable Angina (class IIa) 1. Clopidogrel when aspirin is absolutely contraindicated 2. Long-acting non-dihydropyridine calcium antagonists † instead of beta blockers as initial therapy B 3. In patients with documented or suspected CAD and LDL cholesterol 100–129 mg/dl, several therapeutic options are available: B – a. Lifestyle and/or drug therapies to lower LDL to <100 mg/dl – b. Weight reduction and increased physical activity in persons with the metabolic syndrome – c. Institution of treatment of other lipid or non-lipid risk factors; consider use of nicotinic acid or fibric acid for elevated triglycerides or low HDL cholesterol 4. ACE inhibitor in patients with CAD or other vascular disease Pharmacotherapy for Chronic Stable Angina IIb (weak supportive evidence) – Low-intensity anticoagulation with warfarin in addition to aspirin B III (not indicated) – 1. Dipyridamole B – 2. Chelation therapy B CURE Approach to the treatment of chest pain OXYGEN DEMAND Double product = (Heart Rate) (systolic blood pressure) BETA BLOCKERS Effects of β-blockade on ischemic heart Printed from: Drugs for the Heart © 2007 Elsevier Cardiac effects of β-adrenergic blocking drugs at the levels of the SA node, AV node, conduction system, and myocardium Printed from: Drugs for the Heart © 2007 Elsevier Contraindications to β-blockade Printed from: Drugs for the Heart © 2007 Elsevier BETA BLOCKERS STUDIES TIBET (Total Ischemic Burden European Trial) APSIS (The Angina Prognosis Study In Stockholm) ASIST (Atenolol Silent Ischemia Trial) TIBBS (Total Ischemic Burden Bisoprolol Study) IMAGE (International Multicenter Angina Exercise Study) BB for clinical use ACC/AHA 2002 Guideline Update for the Management of Patients With Chronic Stable Angina Comparison of hemodynamic effects of β-blockers and of CCBs Printed from: Drugs for the Heart © 2007 Elsevier CARDIAC VS. VASCULAR Printed from: Drugs for the Heart © 2007 Elsevier Mechanisms of anti-ischemic effects of calcium channel blockers Printed from: Drugs for the Heart © 2007 Elsevier Verapamil and diltiazem have a broad spectrum of therapeutic effects. Printed from: Drugs for the Heart © 2007 Elsevier Contraindications to verapamil or diltiazem Printed from: Drugs for the Heart © 2007 Elsevier Contraindications to dihydropyridines Printed from: Drugs for the Heart © 2007 Elsevier Properties of CCB in clinical use Schematic diagram of effects of nitrate on the circulation Printed from: Drugs for the Heart © 2007 Elsevier Effects of nitrates in generating NO• and stimulating guanylate cyclase to cause vasodilation Printed from: Drugs for the Heart © 2007 Elsevier Current proposals for therapy of nitrate tolerance. Printed from: Drugs for the Heart © 2007 Elsevier A serious nitrate drug interaction Printed from: Drugs for the Heart © 2007 Elsevier Nitrates in Angina Effect of simvastatin on cardiovascular events among patients with and without coronary heart disease (CHD) in the Heart Protection Study Dual role of ACE inhibitors, both preventing and treating cardiovascular disease Printed from: Drugs for the Heart © 2007 Elsevier Post-infarction remodeling Printed from: Drugs for the Heart © 2007 Elsevier ACC/AHA Guidelines for Treatment of Risk Factors (class I) 1. Treatment of hypertension according to Joint National Conference VI guidelines A 2. Smoking cessation therapy B 3. Management of diabetes C 4. Comprehensive cardiac rehabilitation program (including exercise) B 5. LDL-lowering therapy in patients with documented or suspected CAD and LDL cholesterol ≥130 mg/dl, with a target LDL of <100 mg/dl A 6. Weight reduction in obese patients in the presence of hypertension, hyperlipidemia, or diabetes mellitus C ACC/AHA Guidelines for Treatment of Risk Factors (class IIa) 1. In patients with documented or suspected CAD and LDL cholesterol 100–129 mg/dl, several therapeutic options are available: B – – a. Lifestyle and/or drug therapies to lower LDL to <100 mg/dl B b. Weight reduction and increased physical activity in persons with the metabolic syndrome B – c. Institution of treatment of other lipid or nonlipid risk factors; consider use of nicotinic acid or fibric acid for elevated triglycerides or low HDL cholesterol B 2. Therapy to lower non-HDL cholesterol in patients with documented or suspected CAD and triglycerides >200 mg/dl, with a target non-HDL cholesterol <130 mg/dl B 3. Weight reduction in obese patients in the absence of hypertension, hyperlipidemia, or diabetes mellitus C ACC/AHA Guidelines for Treatment of Risk Factors (class IIb) 1. Folate therapy in patients with elevated homocysteine levels C 2. Identification and appropriate treatment of clinical depression to improve CAD outcomes C 3. Intervention directed at psychosocial stress reduction C ACC/AHA Guidelines for Treatment of Risk Factors (class III) 1. Initiation of hormone replacement therapy in postmenopausal women for the purpose of reducing cardiovascular risk A 2. Vitamins C and E supplementation A 3. Chelation therapy C 4. Garlic C 5. Acupuncture C 6. Coenzyme Q C Specific Goals for Risk Reduction Strategies in Patients with Chronic Stable Angina Smoking Complete cessation Blood pressure <140/90 or 130/85 mm Hg if heart failure or renal insufficiency; <130/85 mm Hg if diabetes Lipid management Primary goal: LDL <100 mg/dl Secondary goal: If triglycerides ≥200 mg/dl, then non-HDL should be <130 mg/dl Physical activity Minimum goal: 30 min 3 or 4 d/w Optimal goal: daily Weight management BMI 18.5–24.9 kg/m2 Diabetes management HbA1c <7% Specific Goals for Risk Reduction Strategies in Patients with Chronic Stable Angina Antiplatelet agents/anticoagulants : All patients: indefinite use of aspirin 75– 325 mg per day if not contraindicated. Consider clopidogrel as an alternative if aspirin is contraindicated. Manage warfarin to international normalized ratio = 2.0 to 3.0 in patients after myocardial infarction when clinically indicated or for those not able to take aspirin or clopidogrel ACE inhibitors: Treat all patients indefinitely after myocardial infarction; start early in stable high-risk patients (anterior myocardial infarction, previous myocardial infarction, Killip class II [S3 gallop, rales, radiographic CHF]). Consider chronic therapy for all other patients with coronary or other vascular disease unless contraindicated. Use as needed to manage blood pressure or symptoms in all other patients Beta blockers: Start in all post-myocardial infarction and acute patients (arrhythmia, LV dysfunction, inducible ischemia) at 5–28 days. Continue 6 mo minimum. Observe usual contraindications. Use as needed to manage angina, rhythm, or blood pressure in all patients ACC/AHA Guidelines for Echocardiography, Treadmill Exercise Testing, Stress Radionuclide Imaging, Stress Echocardiography Studies, and Coronary Angiography During Patient Follow-Up 1. Chest radiograph for patients with evidence of new or worsening CHF C 2. Assessment of LV ejection fraction and segmental wall motion by echocardiography or radionuclide imaging in patients with new or worsening CHF or evidence of intervening myocardial infarction by history or ECG C 3. Echocardiography for evidence of new or worsening valvular heart disease C 4. Treadmill exercise test for patients without prior revascularization who have a significant change in clinical status, are able to exercise, and do not have any of the ECG abnormalities listed in No. 5 ACC/AHA Guidelines for Echocardiography, Treadmill Exercise Testing, Stress Radionuclide Imaging, Stress Echocardiography Studies, and Coronary Angiography During Patient Follow-Up 5. Stress radionuclide imaging or stress echocardiography procedures for patients without prior revascularization who have a significant change in clinical status and are unable to exercise or have one of the following ECG abnormalities: C – – – – a. Preexcitation (Wolff-Parkinson-White) syndrome b. Electronically paced ventricular rhythm c. More than 1 mm of rest ST depression d. Complete left bundle branch block 6. Stress radionuclide imaging or stress echocardiography procedures for patients who have a significant change in clinical status and required a stress imaging procedure on their initial evaluation because of equivocal or intermediate-risk treadmill results C 7. Stress radionuclide imaging or stress echocardiography procedures for patients with prior revascularization who have a significant change in clinical status C 8. Coronary angiography in patients with marked limitation of ordinary activity (CCS class III) despite maximal medical therapy Chronic stable angina NEW THERAPIES Myocardial ischemia: Sites of action of anti-ischemia medication Development of ischemia Consequences of ischemia ↑ O2 demand • • • • Heart rate Blood pressure Preload Contractility Ischemia (Ca2+ overload) ↓ O2 supply Conventional anti-ischemic medications ß blockers Nitrates Ca++ blockers • Electrical instability • Myocardial dysfunction (↓ systolic function/ ↑ diastolic stiffness) Ranolazine Compression of nutritive blood vessels (Stone, 2004) Consequences associated with dysfunction of late sodium current • Diseases (eg, ischemia, heart failure) Na+ channel • Pathological milieu (reactive O2 species, (Gating mechanism ischemic metabolites) malfunction) • Toxins and drugs (eg, ATX-II, etc.) Mechanical dysfunction Oxygen supply and demand • Abnormal contraction • Increase ATP and relaxation • ↑ diastolic tension (↑LV wall stiffness) consumption • Decrease ATP formation Electrical instability • Early after potentials • Beat-to-beat ΔAPD • Arrhythmias (VT) Diastolic relaxation failure increases oxygen consumption and reduces oxygen supply Increased myocardial tension during diastole: – Increases myocardial O2 consumption – Compresses intramural small vessels Reduces myocardial blood flow – Worsens ischemia and angina Ranolazine: Mechanism of action Ischemia ↑ Late INa Ranolazine inhibits the late inward Na current Na+ overload Ca2+ overload Diastolic relaxation failure (increased diastolic tension) Extravascular compression Monotherapy with ranolazine increases exercise performance at trough and peak: MARISA Placebo 500 mg bid 1000 mg bid 1500 mg bid Peak Time, sec Trough 560 520 480 440 400 ** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** ** Exercise duration Time to angina Time to 1mm ST depression n=175, **p <0.01 vs placebo; ***p <0.001 vs. placebo Exercise duration Time to angina Time to 1mm ST depression Chaitman et al JACC 2004;43:1375 Combination regimen of ranolazine with: ► Atenolol 50 mg qd, or ► Diltiazem 120 mg qd, or (CARISA) ► Amlodipine 5 mg qd Change from baseline, sec Placebo 150 Trough * * 750 mg bid 1000 mg bid Peak ** ** * * *** *** * ** 100 50 Exercise duration Time to angina Time to 1-mm ST depression n=791 *p <0.05; **p ≤0.01; ***p ≤0.001 vs placebo. Exercise duration Time to angina Time to 1-mm ST depression Chaitman et al. JAMA 2004;291:309 Effect of ranolazine in patients with refractory angina despite maximum amlodipine therapy: ERICA p=0.48 p=0.028 6 5 4 3 2 1 0 Amlodipine p=0.18 5.5 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Amlodipine + + Ranolazine Baseline p=0.014 5.0 Amlodipine + Placebo NTG consumption/week Number of NTGs consumed/week Number of angina episodes/week Angina episodes/week Placebo On placebo Amlodipine + Ranolazine On ranolazine Stone et al. Circulation 2005;112:II-748 TMR Surgical surgeons use the laser to make between 20 and 40 tiny (one-millimeter-wide) Percutaneous TMR Percutaneous Rationale improved perfusion by stimulation of angiogenesis potential placebo effect anesthetic effect mediated by the destruction of sympathetic nerves carrying pain-sensitive afferent fibers Peri-procedural infarction. EECP EECP Increases arterial blood pressure and retrograde aortic blood flow during diastole (diastolic augmentation). Cuffs are wrapped around the patients legs and sequential pressure (300mmHg) is applied in early diastole. Patient selection Angina class III/IV – Refractory to medical therapy – Reversible ischemia of the free wall – not amenable for revascularization Excluded if LVEF<20% or had current major illness ACC/AHA Guidelines for Revascularization with PCI and CABG in Patients with Stable Angina (class I) 1. CABG for patients with significant left main coronary disease A 2. CABG for patients with triple-vessel disease. The survival benefit is greater in patients with abnormal LV function (ejection fraction <0.50)A 3. CABG for patients with double-vessel disease with significant proximal LAD CAD and either abnormal LV function (ejection fraction less than 50%) or demonstrable ischemia on noninvasive testing A 4. Percutaneous coronary intervention for patients with double-or triple-vessel disease with significant proximal LAD CAD, who have anatomy suitable for catheterbased therapy and normal LV function and who do not have treated diabetes B ACC/AHA Guidelines for Revascularization with PCI and CABG in Patients with Stable Angina (class I) 5. PCI or CABG for patients with single- or doublevessel CAD without significant proximal LAD CAD but with a large area of viable myocardium and high-risk criteria on noninvasive testing B 6. CABG for patients with single- or double-vessel CAD without significant proximal LAD CAD who have survived sudden cardiac death or sustained ventricular tachycardia C 7. In patients with prior PCI, CABG or PCI for recurrent stenosis associated with a large area of viable myocardium or high-risk criteria on noninvasive testing C 8. PCI or CABG for patients who have not been successfully treated by medical therapy and can undergo revascularization with acceptable risk B QUESTIONS??