بسم الله الرحمن الرحيم

1. بسم الله الرحمن الرحيم

2. Current Treatment of Stable Angina By Ahmed Shafea Ammar MD, FACC

3. Definition of Angina

4. Definition • Chronic stable angina (CSA) is defined as the predictable occurrence with exertion or emotional upset of pressure or a squeezing sensation in the substernal area of the chest and adjacent areas, due to transient myocardial ischemia. • Angina equivalents (exertional breathlessness, fatigue, and/or nausea) may also occur with physical activity or emotional stress.

5. Clinical Classification of Chest Pain

6. Endothelial Dysfunction Atherosclerosis Timeline Complicated Lesion/ Rupture Foam Cells Fatty Streak Intermediate Lesion Atheroma Fibrous Plaque From First Decade From Third Decade From Fourth Decade Adapted from Pepine CJ. Am J Cardiol. 1998;82(suppl 104).

7. Which Plaque Ruptures??? Vulnerable vs Stable Atherosclerotic Plaques Vulnerable Plaque Lumen LipidCore • Thin fibrous cap • Inflammatory cell infiltrates: • proteolytic activity • Lipid-rich plaque Fibrous Cap Stable Plaque Lumen • Thick fibrous cap • Smooth muscle cells: • more extracellular matrix • Lipid-poor plaque Lipid Core Fibrous Cap Libby P. Circulation. 1995;91:2844-2850.

8. Epidemiology of Chronic Angina • AHA reports that at least 6.6 million Americans suffer with angina pectoris • Despite therapeutic advances • > 13 million episodes of angina a week in the US • > 1000 episodes of angina every minute • Growing prevalence of chronic angina due to reductions in cardiovascular mortality • Improved treatment of angina is an important goal

9. Comorbid Conditions Complicate Therapy Studies of VA patients with CAD demonstrate the following comorbidity incidence rates • Diabetes: 26% to 31% • COPD: 13% to 22% • Peripheral vascular disease: 16% to 28% • Congestive heart failure: 20% • Rumsfeld, 1999.

10. Noninvasive Risk Stratification High-Risk (>3% annual mortality rate) 1. Severe resting LV dysfunction (LVEF < 35%) 2. High-risk treadmill score (score  -11) 3. Severe exercise LV dysfunction (LVEF < 35%) 4. Stress-induced large perfusion defect (particularly if anterior) 5. Stress-induced multiple perfusion defects of moderate size 6. Large, fixed perfusion defect with LV dilation or increased lung uptake (thallium-201) 7. Stress-induced moderate perfusion defect with LV dilation or increased lung uptake (thallium-201) 8. Echocardiographic wall motion abnormality (involving > 2 segments) developing at low dose of dobutamine ( 10 mg/kg/min) or at low heart rate (< 120 beats/min) 9. Stress echocardiographic evidence of extensive ischemia

11. Intermediate-Risk (< 3% annual mortality rate) 1. Mild-moderate resting LV dysfunction (LVEF - 35% to 49%) 2. Intermediate-risk treadmill score (-11 score 5) 3. Stress-induced moderate perfusion defect without LV dilatation or increased lung uptake (thallium-201) 4. Limited stress echocardiographic ischemia with a wall motion abnormality only at higher doses of dobutamine involving  two

12. Low-Risk (< 1% annual mortality rate) 1. Lowest treadmill score (score  5)??? 2. Normal or small myocardial perfusion defect at rest or with stress 3. Normal stress echocardiographic wall motion or no change of limited resting wall motion abnormality during stress ???

13. Prognostic Markers in Exercise TestingThe Duke Treadmill Score (risk calculation) The Duke treadmill score = • exercise time in minutes on Bruce Protocol • minus 5x the ST-segment deviation(during or after exercise, in millimeters) • 4x the angina index(“0” if there is no angina, “1” if angina occurs, and "2" if angina is the reason for stopping the test). • works well for both inpatients and outpatients, and equally well for men and women N Engl J Med 1991;325:849-53

14. Survival According to Risk Groups Based on Duke Treadmill Score 4 –Year Annual Risk Group (Score) Total Survival Mortality Low ( +5) 62% 99% 0.25% Moderate (-10 to +4) 34% 95% 1.25% High (< -10) 4% 79% 5.00% N Engl J Med 1991;325:849-53

15. Use of Exercise Test Results in Patient Managementneed for additional testing (i.e. stress imaging) predicted average recommendedrisk score annual mortality treatment low <1% per year medical therapy intermediate 1% to 3% cardiac catheterization exercise imaging study high-risk score >3% per year cardiac catheterization * <5% pt with low-risk treadmill score will be identified as high risk after imaging* those with known LV dysfunction should have cardiac catheterization

16. Therapy of Angina

17. Goals of Current Therapy of Angina • Control of Anginal Symptoms • Reduction of MACE

18. For chest pain Nitrates Beta-blockers Calcium antagonists For prognosis Asprin Statin Beta-blockers (after myocardial infarction) Calcium antagonists ACE inhibitor Drugs in angina and secondary prevention of coronary heart disease

19. Strategies to control Anginal Symptoms Antianginal Medications • ß-Blockers, • Nitrates, and • Calcium channel blockers (CCBs) ALL are effective antianginal and anti-ischemic agents. However • There is no evidence that any of these drugs prolong life or reduce the incidence of MI in patients with CSA (J Cardiovasc Pharmacol Ther. 2004)

20. β-Blockers

21. Beta blockers • Beta blockers decrease three major determinants of myocardial oxygen demand • Heart rate • Contractility • Systolic wall tension • Beta blockers also allow improved perfusion of the subendocardium by increasing diastolic perfusion time

22. Rebound Phenomena • Sudden cessation of beta blocker therapy may precipitate myocardial infarction • Those at risk include patients with angina and men over 50 years.

23. Contraindications • Asthma • Peripheral Vascular Disease • Relative contraindication • Raynauds Syndrome • Heart failure • Those patients who are dependent on sympathetic drive • Bradycardia / Heart block

24. Adverse Drug Reactions • Tiredness /fatigue • Impotence • Bradycardia • Bronchospasm

25. Nitrates

27. Veins Arterioles Coronary vessels Dilation of venous capacitance vessels Dilation of peripheral resistance vessels Dilation of coronary vessels Pre-load reduction After-load reduction Vasal resistance Coronary/Venous spasm PCP and PAP Resistance against cardiac-output Coronary blood flow Cardiac output End diast. Ventricular pressure Diastolic wall tension Hemodynamic Effects of nitrates Dilatation of vessels O2 consumption O2 supply Optimized O2 balance PCP= pulmonary capillary pressure PAP= pulmonary arterial pressure

28. The Value of Nitrates as Excellent Combination Partners • Nitrates are safe, with rare interactions with other substances (no influence on hepatic metabolism of other drugs). • Nitrates have no effect on plasma lipid & glucose levels such as beta-blockers, & do not provoke angina or peripheral edema such as calcium-antagonists. • Nitrates have beneficial CV effects, which are complementary to the effects of other CV drugs. • Nitrates are cost-effective.

29. Nitrates in management of stable angina • For Immediate relief Treatment with glyceryl trinitrate/ISDN that can be given as a spray or sublingually. • Long term Prophylaxis Treatment with Isosorbide Mononitrate that can be given either in a short-acting or a sustained release formulation.

30. Different Available Nitrate Preparations • Glyceryl Trinitrate • Isosorbide Dinitrate • Isosorbide Mononitrate

31. “nitrate free interval” • Tolerance may occur to nitrates. • A nitrate free interval of at least 8 hours has been recommended between doses. • After overnight free period, sensitivity returns the next day.

32. Headache Increase dose slowly Hypotension GTN syncope Adverse Drug Reactions

33. Calcium Channel Blockers

35. Anti-anginal Effects of CCBs • CCBs reduce vascular tone and so produce vasodilatation • reduce after load and so myocardial work load • Rate limiting CCBs reduce myocardial contractility • reduce myocardial oxygen requirements • Rate limiting CCBs reduce heart rate • reduce myocardial oxygen requirement • CCBS may also produce coronary vasodilatation • Of little importance or even dangerous

36. Adverse Drug Reactions • Ankle oedema • Affects 15-20% of patients and does not respond to diuretics • Headache • Flushing • Palpitation

37. Contraindications • Evidence that the use of short acting CCBs (nifedipine) may precipitate acute MI or stroke • Post MI • May increase morbidity and mortality in patients with impaired LV function • Unstable angina • Evidence that dihydropyridines may increase infarction rate and death in the unstable patient

38. Beta-blockers vs. calcium antagonists: angina relief. Reproduced from ACC/AHA 2002 guideline update for the management of patients with chronic stable angina,3 with permission.

39. Beta-blockers vs. calcium antagonists: exercise time to 1 mm ST-depression. Reproduced from ACC/AHA 2002 guideline update for the management of patients with chronic stable angina,3 with permission.

40. New drugs for the treatment of angina pectoris and mechanisms of action

41. Strategies to Reduce MACE1-Risk Factors Management2- Asprin3- Statin4- B- blocker5- ACEI6- Surgery7- ?? DES

42. Risk Factor Management 1 (Level B), ↓1 year mortality by 50% 2 ( Level A), ↓ CV mortality by 18-20%) Level A = multiple RCTs Level B = single RCT or non RTs Level C= expert openion

43. Risk Factor Management 3 4 ( Level B) 5 ( Level C)

44. Risk Factor Management 6 LDL <100 mg/dl (Level A)

45. Risk Factor Management 7

46. ASPRIN • Daily aspirin (81-325 mg) reduced CV mortality and morbidity with an ARR of 12 /1000 patients treated during a 15-month period. (Lancet. 1992; 340: 1421–1425)

47. STATIN • No specific trials with lipid-lowering agents have been conducted in patients with CSA. However, in the 4S trial, many patients had CSA and experienced a reduction in angina as well as in MACE • Current guidelines recommend a target fasting LDL cholesterol level of <100 mg/dL in patients with CSA. • The most recent NCEP-ATP III directive suggests a target of LDL <70 mg/dL for high-risk CAD patients.

48. Β-blockers • ß-Blockers have been shown to improve survival and reduce hospitalization in HF patients with an LVEF 40% and in survivors of acute MI. • BB should be used as first-line therapy in patients with CSA who have reduced LV systolic function, provided that such patients are on background treatment with ACEI. • Practice guidelines recommend that ß-blockers are the first choice of therapy for uncomplicated CSA. (N Engl J Med. 2005; 352: 2524–2533)

49. ACEI • ACEI should be used in all patients with CSA, who have : previous MI diabetes, hypertension, proteinuria, CKD LVEF <40% (Circulation. 2005;112:e255-e259.) • In older patients with CAD, routine use of ACEI has been recommended on the basis of the positive results of the HOPE and EUROPA trials.

50. CABG & PCI • PCI and CABG relieve angina in 80% to 90% of patients. • However, compared with medical therapy, these procedures do not prolong life or reduce the incidence of MI, except in patients with LMC disease and in those with 2- or 3-vessel disease with decreased LV function (J Cardiovasc Pharmacol Ther. 2004)