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Ischemic Heart Disease (IHD): Angina Pectoris PowerPoint Presentation
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Ischemic Heart Disease (IHD): Angina Pectoris

Ischemic Heart Disease (IHD): Angina Pectoris

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Ischemic Heart Disease (IHD): Angina Pectoris

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  1. Ischemic Heart Disease (IHD): Angina Pectoris • Angina pectoris is the collection of symptoms resulting from myocardial ischemia as a result of atherosclerosis of coronary arteries • IHD is also called coronary artery disease (CAD) or coronary heart disease (CHD) • CHD includes together with angina, acute coronary syndrome (ACS) • ACS comprises unstable angina (USA), acute myocardial infarction (MI), acute HF, and sudden death

  2. Features of Angina Pain • Location: Over the sternum or near to it, Small area of chest (≤3 cm), entire right/left side, leg pain • Radiation to left shoulder/arm, jaw, tongue, teeth • Duration: Ranges from seconds to hours • Descriptors: Sharp, sticking, stabbing, knifelike, pricking, gas • Triggers: Exercise, heavy meals, body position, cold weather • Nitroglycerin relief: after 45 seconds-5 min • ECG: ST-depression, T-wave inversion

  3. Causes of Angina Pectoris • Typical angina results from advanced coronary atherosclerosis in at least one moderately sized epicardial coronary artery • In general, obstructions in diameter of 60% or greater are likely to be associated with angina, whereas lesions of less than 50% ordinarily do not cause ischemia • Severe angina (chest pain caused by little exertion) is usually associated with coronary obstructions of 80% to 100% • Patients are often characterized as having one-, two-, or three-vessel disease, as determined by coronary arteriography

  4. Causes of Angina Pectoris • A, Several high-grade narrowing of a right coronary artery. • B, Severe (>90%) stenosis (arrows) of a left anterior descending coronary artery

  5. Coronary Stenosis • Coronary artery obstructions are capable of changing caliber, • Constriction or narrowing of a preexisting lesion can be a factor in precipitating angina and myocardial ischemia Nitrates Eccentric Concentric

  6. Risk Factors for Coronary Artey Disease

  7. Non-standard CAD Risk Factor

  8. AHA/ACC Guidelines for the Secondary Prevention for Patients with Coronary and Other Atherosclerotic Vascular Disease

  9. Myocardial Oxygen Supply & Demand Oxygen Supply Oxygen Demand • Cardiac Contractility/Rate • Ventricular Wall Tension (Systolic & Diastolic) • Coronary Blood Flow • Oxygen Extraction & Saturation

  10. Treatment Overview • Medical management should be individualized • Risk factor modification is indispensible for prevention & treatment of CHD • Goal of therapy:reduction of the number, severity, & duration of anginal attacks • Six drug classes are used alone/ in combinations: • Nitrates • β-blockers • Calcium channel blockers • Antiplatelets, Anticoagulants • ACE inhibitors

  11. Diagnostic Procedures • Exercise tolerance test: ECG signs of ischemia, angina • HR-SBP product is usually used • Myocardial imaging, echocardiographic or nuclear, preferred to exercise tolerance • Pharmacologic stress (e.g, dobutamine or adenosine injection) can be used • Cardiac catheterization & subsequent angiography can detect coronary artery spasm

  12. Anti-Ischemic Drug TherapyNITRATES • Treatment of all anginal syndromes • Mechanism & Properties: • Inhibition of thromboxane synthase • Venodilation is more than arterial because the latter needs higher plasma nitrate level • NO production→ + vascular SM –SH groups → S-nitrothiols → Activation of Guanylate cyclase→ Increased intracellular cGMP • Venous dilation →lowered preload →reduction of ventricular filling pressure →decreased myocardial O2 consumption → anginal pain relief

  13. NITRATES • Coronary artery vasodilation → increased coronary blood flow increased oxygen supply • Angiographic studies showed that coronary arteries with eccentric atherosclelerotic lesion will dilate in response to nitrates • Another antianginal agent (ß-blocker or CCB) must provide the antianginal effect during the nitrate-free period

  14. Short-Acting NitratesSublingual Nitroglycerin (NTG) • Dose: mostly 0.4 mg, relief of pain, objective hemodynamic effect (10 mm Hg drop, ↑HR) • Onset: 1-3 min, duration:10-30 • Prevention of attack: To be taken 5-10 min before the exertion that possibly precipitate angina • Instructions to Patient: • Sit immediately, place NTG tablet under tongue • Max three tablets over 15 min • If pain persists >30 min →suspected MI • NTG tablets are volatile →a tablet left outside loses activity in min • An open bottle →use for 6-12 months

  15. Nitroglycerin Lingual Spray • NTG lingual spray, 0.4 mg/metered dose is an alternative for SL NTG • Each canister has 200 metered dose/3 years shelf-life • Spray a single dose under or onto the tongue • NTG lingual spray should not be inhaled • Max dose: three sprays over 15 min

  16. Long-Acting Nitrates • NTG: SR capsule, Topical ointment, transdermal patches • Isosorbide Dinitrate (ISDN): oral, SR, SL, and chewable • Isosorbide Mononitrate (ISMN): SR tab, rapid-release tablets Long-acting nitrates are the prevention corner stone therapy of all types angina • CCB can be an alternative especially if angina patient has improperly controlled HTN

  17. Side Effects to Nitrates • Hypotension • Headache: tolerance develops after few weeks • Dizziness • Syncope/fainting necessitates dosage reduction • Severe hypotension & bradycardia caused cardiac arrest in patients experiencing MI • NTG-induced vaso-vagal response → NTG syncope → leg elevation, atropine, fluids • Met-Hbemia is important when large IV NTG doses used

  18. Nitrate Tolerance • Tolerance is unlikely to occur with NTG (SL, oral spray), and SL isosorbide dinitrate • Tolerance is likely with long-acting oral nitrates (ISMN) & transdermal patches • 12 hour NTG transdermal patches’ intermittent therapy minimize tolerance • Intravenous NTG used in unstable angina (USA) & severe HF is associated with tolerance • 12 hour intermittentintravenous NTG limit nitrate tolerance

  19. Nitrate Tolerance Minimization • Nitrate-free interval of 10-12 hours minimize tolerance to therapeutic activity • Lowest effective nitrate dose lower tolerance • ß-blocker or CCB is given to provide anginal protection during nitrate-free period • Long-acting nitrates have no evidence of causing tolerance to SL nitrates’ use

  20. MECHANISM OF Nitrate Tolerance • Depletion of vascular –SH groups, plasma volume expansion, neurohormonal activation • Nitrates increases superoxide anion (O2-) + NO → peroxynitrite producing: • Decreased endothelial NO production • Increased sympathetic & RAA systems • Increased vasoconstrictor responsiveness • Peroxynitrite-dependent assumption stimulates the question: dose nitrate have long-term detrimental effects?

  21. ISOSORBIDE DINITRATE & MONONITRATE (ISDN & ISMN) • ISDN oral formulation is used usually three times a day especially in severe angina • Usually ISDN is taken at 7 AM, Noon & 5 PM to allow 12 hr nitrate-free period • ISDN can be given twice/day in moderate severity angina • Isosorbide mononitrate (ISMN) can be given once or twice/day (early morning & 7 hrs later) • ISMN has better patient compliance

  22. ß-ADRENERGIC BLOCKERS • Decreased myocardial oxygen consumption by lowering adrenergic-related HR, BP & contractility • ß2-adrenergic receptors were shown to be present in the heart by 10-40%, possibly augment cardiac contractility & HR • In chronic angina: ß-blockers should be given before nitrates & CCBs • ß-blockers are more effective than the other two agents in lowering incidence of anginal episodes • The three classes are similar in mortality reduction • They lower CV morbidity/mortality in HTN, HF, or MI patients

  23. ß-ADRENERGIC BLOCKERS THERAPEUTIC ENDPOINT • Anginal attacks frequency & NTG consumption are indices for therapeutic efficiency of antianginals • Reduction in resting HRis best monitored to adjust ß-blockers’ dose • Dose can be increased till HR is 55 b/min, even 50 b/min is acceptable for asymptomatic patients • ß-blockers with ISA do not lower resting HR • Exercise testing is the best, though least practical: • Reduction of exercise ST-depression • HR-SBP product usually decreases (lowered wall tension & HR)

  24. β-Adrenergic BlockersDosing • β-blocker pharmacodynamic actions are longer than their plasma half-lives • Usually taken once to twice daily for angina • Atenolol t1/2 is 10 hours but clinical evidence support the effectiveness of once daily regimen • Propranolol is of short 2-3 hrs t1/2, yet its BP/HR lowering effects are pronounced for 12 hours • Clinical evidence support the effectiveness of twice daily regimen of propranolol

  25. β-Adrenergic BlockersCardio-selective & Contraindications • Cardio-selective ß-blockers did NOT produce adverse respiratory effects in moderate respiratory diseases (Meta-analysis) • Cardio-selective ß-blockers low inhibition of ß2-induced peripheral vasodilation (α-vasoconstrictn) • Atenolol/acebutalol/metoprolol preferred in peripheral vascular disease & Raynaude’s disease • DIABETES is NOT a contraindication for ß-blockers • Lower mortality in diabetics after MI • CAD is more severe in diabetics & has worse prognosis over that developed in non-diabbetics

  26. β-Adrenergic Blockers • ISA ß-blockers→less effect on lipid/glucose • ISA ß-blockers→ less bradycardia →less effective in angina or worsen angina (better avoided) • ß-blockers abrupt withdrawal can be serious in severe atherosclerosis/USA→severe CV effects like acute MI & sudden cardiac death • ß-blockers withdrawal schedule can be a two-weeks four-steps on 2-3 days schedule

  27. CALCIUM CHANNEL BLOCKERS • Amlodipine & felodipine (DHPs) are the only CCBs that can be used in HF patients • Nifedipine IR, diltiazem & verapamil should be avoided in HF patients • INDICATIONS: Vasospastic & classical exertional angina • CCBs by arterial dilation →decrease myocardial O2 demand • CCBs cause coronary dilation Coronary → increase myocardial O2 supply • Vasospasm can occur at atherosclerotic site, CCB can cause dilation

  28. CALCIUM CHANNEL BLOCKERS • NIFEDIPINE: 10%nifedipine patients experience angina worsening because of powerful dilation→ reflex increase in HR → increase O2 demand → can cause acute MI • This is frequent with IR preparations • IR nifedipine no longer used for any disease • SR nifedipine is used • Side Effects:hypotension, dizziness (15%), facial flushing & headache & nausea • Peripheral edema with DHPs • Constipation with verapamil

  29. CALCIUM CHANNEL BLOCKERScontraindications • Severe hypotension • Severe aortic stenosis • Extreme bradycardia • Moderate to severe HF • Cardiogenic shock • Sick sinus syndrome • Second/third degree A-V block

  30. COMBINATION THERAPY • ß-blockers-nitrate-CCBtriple therapy is an option to maximize benefit & lower side effects • Disadvantages: Cost, possible additive side effects (HF worsening by ß-blocker-CCB) • Excessive vasodilation-bradycardia in triple therapy can be minimized using CCB with less potent vasodilating properties • Initial therapy in chronic angina: ß-blocker • Then Nitrate or CCB is added according to patient status (No fixed guidelines)

  31. COMBINATION THERAPY • Nitrates, as a second class, are preferred in patients with LV dysfunction • CCBs, as a second class, are preferred whenever further BP control is needed • Two CCBs combination: Nifedipine with verapamil or diltiazem lower dizziness & effects on cardiac conduction & contractility • Two CCBs combination used when standard triple therapy (at max tolerable individual doses) is still ineffective

  32. Ranolazine (FDA Approval 2006)Mechanism of Action • Unlike traditional antianginal agents, it does not have any appreciable effects on heart rate, arterial resistance vessels, the myocardial inotropicity, or coronary blood flow • It does NOT affect blood pressure or heart rate • Ranolazine does not affect myocardial oxygen supply or demand • Early preclinical work showed that it inhibits fatty acid oxidation, however, at higher plasma level than those used therapeutically

  33. Ranolazine (FDA Approval 2006)Mechanism of Action • It is now known that ranolazine's anti-ischemic effects are modulated through inhibition of the late sodium current (INa) • By inhibiting late sodium entry, and hence calcium overload during ischemia

  34. Ranolazine (FDA Approval 2006)Mechanism of Action • Ranolazine effectively inhibits the consequences of ischemia as decreased microvascular perfusion, as well as increased myocardial oxygen demand • This novel mechanism of action offers the possibility of complementary effects when added to more traditional antianginal agents which act through their hemodynamic actions

  35. Vasculoprotective Drug Therapy

  36. Rationale for CONVERTING ANGIOTENSIN ENZYME INHIBITORS • ACEIs reduced MI by 23% in HF patients → Are ACEIs beneficial in LV dysfunction-free CAD patients and post-acute MI patients? The HOPE study: • 9,297 patients with chronic CADandno HF • Ramipril reduced incidence of death, MI, stroke, need for revascularization, and angina worsening • Benefit was independent of BP lowering effect • Patients were on standard angina therapy

  37. CONVERTING ANGIOTENSIN ENZYME INHIBITORS EUROPA study: 12,218 PATIENTS, 4.2 YEARS • Perindopril in stable angina with no HF • Reduction of combined incidence CV death, MI & cardiac arrest • Similar to HOPE study, is this beneficial effect class-related? • Tissue binding & inhibition of ACE in myocardium & endothelium varies among different ACEIs For ARBs, there is no clinical trials yet

  38. Antiplatelet TherapyAspirin • Platelet activation produces coronary occlusion either by formation of a platelet plug or through release of vasoactive compounds from the platelets • A single 100-mg aspirin dose virtually eliminates thromboxane A2 production, whereas doses below 100 mg result in a dose-dependent reduction in thromboxane A2 synthesis • Determine the effect of aspirin doses on the TXA2 to PGI2 • Selective inhibition of platelet-generated TXA2 synthesis has been shown with 75 mg of controlled-release aspirin daily

  39. Aspirin • It has been believed that higher doses of aspirin would produce a higher level of efficacy than low doses • However, all available literature indicates that low dosages of aspirin (75–325 mg/day) are as effective as higher dosages (625–1,300 mg/day) in the treatment of angina • Therefore, current guidelines recommend a daily dosage of 75 to 162 mg orally for the prevention of MI and death in patients with CAD

  40. Clopidogrel • Clopidogrel (Plavix), a thienopydridine, inhibits platelet function in vivo via noncompetitive antagonist of the platelet ADP receptor • Clopidogrel at a dosage of 75 mg orally every day was demonstrated in one study to be slightly more effective than aspirin in the secondary prevention of MI and death in patients with various manifestations of atherosclerotic vascular disease • Clopidogrel historically was to serve as an alternative antiplatelet agent in patients with a true contraindication to aspirin

  41. Clopidogrel • The magnitude of difference in benefit seen with clopidogrel was quite small and not sufficient to justify its broad scale use in the treatment of CAD • Based on this study, the role of clopidogrel historically was to serve as an alternative antiplatelet agent in patients with a true contraindication to aspirin

  42. Aspirin/Clopidogrel Combination • The combination of aspirin and clopidogrel was compared with aspirin alone in patients with acute coronary syndromes without ST-segment elevation in the CURE study for an average of 9 months • The combination of aspirin and clopidogrel significantly reduced CVS death, nonfatal MI, or stroke • The results of the CURE study were confirmed in the Clopidogrel for Results of Events During Observation (CREDO) trial where patients with ACS who were treated with percutaneous coronary stent intervention received aspirin/clopidogrel for 1 year • Patients receiving both aspirin and clopidogrel for 1 year had a lower incidence of death, MI, and stroke in comparison to patients who only received aspirin

  43. Aspirin/Clopidogrel Combination in Chronic CAD • Given the beneficial effects seen in patients with recent ACS, and in patients with PCI plus stent placement • Is dual therapy with aspirin plus clopidogrel would be superior to aspirin in the treatment of chronic stable CAD • In the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial, 15,063 patients with documented vascular disease (CAD, cerebrovascular, peripheral arterial disease), or no documented vascular disease but with multiple cardiovascular risk factors, were assigned to aspirin alone or aspirin plus clopidogrel for an average of 28 months duration

  44. Aspirin/Clopidogrel Combination in Chronic CAD • Unlike the results from ACS studies, however, the combination of aspirin plus clopidogrel did NOTreduce the incidence of the primary endpoint (risk of death, MI, stroke, or coronary revascularization) as compared with aspirin alone • In a secondary analysis of patients who entered the trial with documented vascular disease, dual therapy did produce statistically significant reductions in the primary endpoint as compared with aspirin

  45. VARIANT ANGINA (CORONARY ARTERY SPASM) • ST-segment elevation is the cardinal mark for variant angina • It results from severe large coronary artery segmental spasm with transient total occlusion • Transient arrhythmias & conduction disturbances may be observed during pain or no symptoms • ↑ HR-SBP product characterizing stable angina during pain does not occur with variant angina • Angiography can show the vasospasm • Ergonovine test can provoke the unpredictable coronry vasospasm by stimulating α-adrenergic & 5-HT receptors

  46. VARIANT ANGINA therapy • CCBs are usually preferred over nitrates or ß-blockers • All CCBs are equally effective but intrinsically long-acting or SR forms are preferred • CCB-Nitrate combination should be tried when max CCB dose is still ineffective • Aspirin is indicated for variant angina • ß-blockers mostly worsen variant angina by unmasking α-vasoconstriction by ß2-blockade • Cardioselective ß-blockers can worsen variant angina

  47. VARIANT ANGINA therapyPrognosis • 50% of variant angina patients undergo full spontaneous recovery via unknown mechanism • This occurs with isolated vasospasm without atherosclerosis (short-duration symptoms) • Therapy can be stopped, after gradual tapering, if patients are free from pain, significant arrhythmias, or silent ischemic episodes for one year • Risk factor modification may enhance variant angina remission

  48. VARIANT ANGINA therapyDevelopment of mi • Variant angina can proceed to MI or myocardial death especially in multi-vessel coronary spasm • In a small group of hospitalized variant angina patients, 76% experienced morbid cardiac events (acute MI, sudden death, & CA bypass graft) within a month of angina onset • Aggressive CCB+NTG infusion during the early stages improve prognosis

  49. Acute Coronary syndrome (ACS)