بسم الله الرحمن الرحيم

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

Definition of Angina

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.

Clinical Classification of Chest Pain

Atherosclerosis Timeline FoamCellsFattyStreakIntermediateLesionAtheromaFibrousPlaque ComplicatedLesion/Rupture Adapted from Pepine CJ. Am J Cardiol. 1998;82(suppl 104). From First Decade From Third Decade From Fourth Decade Endothelial Dysfunction

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

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

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.

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

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

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 ???

Prognostic Markers in Exercise Testing The 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

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

Use of Exercise Test Results in Patient Management need for additional testing (i.e. stress imaging) predicted average recommended risk scoreannual 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

Therapy of Angina

Goals of Current Therapy of Angina  Control of Anginal Symptoms  Reduction of MACE

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

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 )

β-Blockers

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

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

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

Adverse Drug Reactions  Tiredness /fatigue  Impotence  Bradycardia  Bronchospasm

Nitrates

Dilatation of vessels Arterioles Dilation of peripheral resistance vessels After-load reduction Resistance against cardiac-output Cardiac output Coronary vessels Dilation of coronary vessels Vasal resistance Coronary/Venous spasm Coronary blood flow Veins Dilation of venous capacitance vessels Pre-load reduction PCP and PAP End diast. Ventricular pressure Diastolic wall tension Optimized O 2 balance O 2 consumption O 2 supply PCP= pulmonary capillary pressure PAP= pulmonary arterial pressure Hemodynamic Effects of nitrates

The Value of Nitrates as Excellent Combination Partners 1.Nitrates are safe, with rare interactions with other substances (no influence on hepatic metabolism of other drugs). 2.Nitrates have no effect on plasma lipid & glucose levels such as beta-blockers, & do not provoke angina or peripheral edema such as calcium- antagonists. 3.Nitrates have beneficial CV effects, which are complementary to the effects of other CV drugs. 4.Nitrates are cost-effective.

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.

Different Available Nitrate Preparations Glyceryl Trinitrate Isosorbide Dinitrate Isosorbide Mononitrate

 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. “nitrate free interval ”

Adverse Drug Reactions  Headache –Increase dose slowly  Hypotension –GTN syncope

Calcium Channel Blockers

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

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

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

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.

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.

New drugs for the treatment of angina pectoris and mechanisms of action DrugProbable mechanism TMZ Metabolic switch IvabradineSlows heart rate; I f channel inhibitor Ranolazin e New: slow sodium channel inhibitor; old: metabolic switch NicorandilK-channel activator and nitrate like properties

Strategies to Reduce MACE 1- Risk Factors Management 2- Asprin 3- Statin 4- B- blocker 5- ACEI 6- Surgery 7- ?? DES

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

Risk Factor Management ( Level B) ( Level C)

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

Risk Factor Management 7 Diabetes Melletis Patients with angina should make efforts to optimize glycemic control. (Level C)

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

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.

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)

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.

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)

Class I Class IIa Patients with 1 or more significant lesions in 1 or more coronary arteries suitable for PCI with a high likelihood of success and low risk of morbidity or mortality.  The vessel (s) to be dilated must subtend a moderate or large area of viable myocardium and have high risk. (Level of Evidence: B) It is reasonable that PCI be performed in patients with CCS class III angina and single-vessel or multivessel CAD who are undergoing medical therapy and who have 1 or more significant lesions in 1 or more coronary arteries suitable for PCI with a high likelihood of success and low risk of morbidity or mortality. (Level of Evidence: B)  The recommendation class has been changed to IIa to reflect published data and Writing Committee consensus.  Criteria regarding viable and high-risk myocardium have been deleted from this recommendation. (2001) (2005)

CABG vs Medical TTT Gr = Coronary anatomy severity groups (9) (J Thorac Cardiovasc Surg 1996) 95% = 95% prox. Stenosis Hazard ratio = MR

CABG vs PCI (J Thorac Cardiovasc Surg 1996)

CABG vs PCI Different trials

ARTS trial, repeat revascularization

Arts MR

CM-58 Percutaneous Coronary Angioplasty Compared With Exercise Training in Patients With Stable Coronary Artery Disease A Randomized Trial (Circulation. 2004;109: )

 ACC/AHA/SCAI 2005 Guideline Update for Percutaneous  Coronary Intervention—Summary Article  A Report of the American College of Cardiology/American Heart Association  Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to  Update the 2001 Guidelines for Percutaneous Coronary Intervention)  WRITING COMMITTEE MEMBERS  Sidney C. Smith, Jr, MD, FACC, FAHA, Chair; Ted E. Feldman, MD, FACC, FSCAI*;  John W. Hirshfeld, Jr, MD, FACC, FSCAI*; Alice K. Jacobs, MD, FACC, FAHA, FSCAI;  Morton J. Kern, MD, FACC, FAHA, FSCAI*; Spencer B. King, III, MD, MACC, FSCAI;  Douglass A. Morrison, MD, PhD, FACC, FAHA, FSCAI*; William W. O’Neill, MD, FACC, FSCAI;  Hartzell V. Schaff, MD, FACC, FAHA; Patrick L. Whitlow, MD, FACC, FAHA;  David O. Williams, MD, FACC, FAHA, FSCAI

PCI vs Medical TTT Meta-analysis of randomised controlled trials (BMJ 321:73-77, 2000)

PCI versus Exercise Training

 O 2 demand +++  O 2 supply ++?+  ATP/O 2 + Evolution of Therapy TREATMENT Likely mechanisms Nitrates  block CABG CCB PCI TMZ TMZIvbradineRanolazineNicorandil

Persistent Angina Despite Current Drug Therapy  Despite use of traditional anti-anginal agents (  -blockers, CCBs, and nitrates), patients still reported an average of 2 anginal attacks/week †  A significant percentage of patients have relative intolerance to full doses of  -blockers, CCBs, and nitrates   -blockers and many CCBs have similar depressive effects on BP, HR and/or AV nodal conduction  It would be desirable to develop an anti-anginal drug without these limitations †Pepine, 1994.

Persistent Angina Despite Percutaneous Intervention (PCI) 1 yr after PCI for...  Symptom relief (N = 1403)  Treatment of acute myocardial infarction (N = 352)... the overall prevalence of angina was 26% Holubkov R, et al. NHLBI Dynamic Registry. Am Heart J. 2002;144: Events, n Angina at follow-up, % Events occurring after post-PCI discharge only MI No Yes CABG No Yes Repeat PCI No Yes Angina at 1-yr follow-up by events during or after initial PCI

Persistent Angina Despite Optimal Revascularization Serruys PW, et al. for the ARTS Study Group. N Engl J Med. 2001;344: yr after optimal revascularization by stenting or surgery for relief of ischemia (ie, not to prolong survival) … ~ 60% to 80% are still taking anti-anginal medications ~ 10% to 20% still have angina T ABLE 3. S TATUS WITH R ESPECT TO A NGINA AND M EDICATION U SE AND Q UALITY OF L IFE A MONG S URVIVING P ATIENTS.* V ARIABLE 12 MO AFTER I NTERVENTION STENTING GROUP SURGERY GROUP P value Free of angina (%) <0.001 Free of antianginal medication (%) <0.001 Free of angina and antianginal medication (%) <0.001

Unmet Need of Chronic Angina  Angina continues in many patients despite medical therapy and mechanical revascularization  The personal burden can deprive many patients of their functional independence, forcing them to downsize their lives  The economic toll of angina places a huge burden on patients, their families, the healthcare system, and society

Unmet Need of Chronic Angina When angina cannot be eliminated by current drugs, it is often their additive effects on BP, HR, AV conduction, and other important side effects (depression, fatigue, sexual/sleep disorders, etc.) that preclude complete relief.

Novel Therapies Needed for a Growing Angina Burden Patients, millions

The 10 most important elements of stable angina management.

Ahmed Shafea MD, FACC