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Chronic Stable Angina: Managing Patients With
Persistent Symptoms
Baltimore, MD
December 3, 2008 3:30 PM – 4:45 PM
Session 6
Session 6: Chronic Stable Angina: Managing Patients With Persistent Symptoms Learning Objectives
• Outline the screening questions listed in the American College of Cardiology/American Heart Association guidelines used to monitor quality of life in patients with chronic stable angina.
• Describe therapies that can be added to conventional medical therapies to improve or restore the quality of life in chronic angina patients who are experiencing worsening symptoms.
Faculty Jerome D. Cohen, MD, FACC, FACP, FAHA Professor Emeritus, Division of Cardiology St. Louis University School of Medicine St. Louis, Missouri Jerome D. Cohen, MD, FACC, FACP, FAHA, is professor emeritus in the Division of Cardiology at St. Louis University School of Medicine. He has been active in cardiovascular research for more than 3 decades. Dr Cohen has authored more than 165 scientific articles and book chapters on heart disease with a primary focus on the prevention of cardiovascular disease, including the treatment of silent myocardial ischemia and risk factors such as hypertension and dyslipidemias. He has been an investigator in many landmark studies of CVD in these areas of investigation. He has served as a member of multiple committees and review boards including the Executive (Writing) Committee and review committee for the 6th and 7th report of the Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure. Dr Cohen is a graduate of The Johns Hopkins University and Washington University School of Medicine. Faculty Financial Disclosure Statement The presenting faculty reported the following: Dr Cohen has no relationships to disclose. Drug List Generic Trade amlodipine Norvasc aspirin various atorvastatin Lipitor clopidogrel Plavix lisinopril Prinivil, Zestril
Generic Trade metoprolol succinate ER Toprol XL nitrates, long acting various ranolazine Ranexa warfarin Coumadin, Jantoven
Suggested Reading List Abrams J. Chronic stable angina. N Engl J Med. 2005;352:2524-2533.
Abrams J, Thadani,U. Therapy of stable angina pectoris: the uncomplicated patient. Circulation. 2005;11;112(15):e255-e259.
Boden WE. Management of chronic coronary disease: is the pendulum returning to equipoise? Am J Cardiol. 2008;101(suppl):69D-74D.
Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007;356:1503-1516.
Fox K, Garcia MA, Ardissino D, et al. Guidelines on the management of stable angina pectoris: executive summary: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. Eur Heart J 2006;27:1341-1381.
Fraker TD Jr, Fihn SD; 2002 Chronic Stable Angina Writing Committee; American College of Cardiology. 2007 chronic angina focused update of the ACC/AHA 2002 guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 guidelines for the management of patients with chronic stable angina. J Am Coll Cardiol. 2007;50(23):2264-2274.
Session 6
Heidenreich PA, McDonald KM, Hastie T, et al. Meta-analysis of trials comparing beta-blockers, calcium antagonists, and nitrates for stable angina. JAMA. 1999;281:1927-1936.
Hemingway H, Shipley M, Britton A, et al. Prognosis of angina with and without a diagnosis: 11 year follow up in the Whitehall II prospective cohort study. BMJ. 2003;327(7420):895-898.
Hilton TC, Chaitman BR. The prognosis in stable and unstable angina. Cardiol Clin. 1991;9(1):27-38.
Jawad E, Arora R. Chronic stable angina pectoris. Dis Mon. 2008:54:671-89.
Klocke FJ, Baird MG, Lorell BH, et al. ACC/AHA/ASNC guidelines for the clinical use of cardiac radionuclide imaging: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (ACC/AHA/ASNC Committee to revise the 1995 guidelines for the clinical use of cardiac radionuclide imaging). J Am Coll Cardiol 2003;42:1318-1333.
Mieres JH, Shaw LJ, Arai A, et al. Role of noninvasive testing in the clinical evaluation of women with suspected coronary artery disease: consensus statement from the Cardiac Imaging Committee, Council on Clinical Cardiology, and the Cardiovascular Imaging and Intervention Committee, Council on Cardiovascular Radiology and Intervention, American Heart Association. Circulation. 2005;111:682-696.
Nash DT, Nash SD. Ranolazine for chronic stable angina. Lancet. 2008;372:1335-1341.
Smith SC Jr, Feldman TE, Hirshfeld JW Jr, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; ACC/AHA/SCAI Writing Committee to Update 2001 Guidelines for Percutaneous Coronary Intervention. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update 2001 Guidelines for Percutaneous Coronary Intervention). Circulation. 2006;113:e166-e286.
Snow V, Barry P, Fihn SD, et al. for the American College of Physicians. American College of Cardiology Chronic Stable Angina Panel. Primary care management of chronic stable angina and asymptomatic suspected or known coronary artery disease: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2004;141(7):562-7.
Thadani U. Current medical management of chronic stable angina. J Cardiovasc Pharmacol Ther. 2004;9(suppl 1): S11-S29.
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1
Chronic Stable Angina: Managing Patients with Persistent Symptoms
Jerome D. Cohen, MD, FACC,FACP, FAHA
Chronic Ischemic Heart Disease: Overview
• Highly prevalent– 9.1 million in the US
• Multifactorial etiology– CAD, hypertension, hypertrophic cardiomyopathy, valvular heart
disease
• High socioeconomic burden– Depression– ↓Quality of life– High costs of care
Heart Disease and Stroke Statistics — 2008 Update, American Heart Association
Case Study:65-year-old African American woman with persistent angina
65-year-old African American woman
New patient
Semi-retired real estate agent, works periodically
Chest pain and short of breath during modest activity for past 6 months.
Presenting complaint
History
65-year-old African American woman
Medical history– Hypertension and
hypercholesterolemia– Post-MI 2 years ago:
• LVEF by ECHO 48%• Angiogram revealed triple-vessel
disease with complex lesions not amenable to PCI
– Triple-vessel CABG (mammaryto LAD). Chest pain recurred 18 months after.
• Repeat CABG ruled out from angiogram .
• Prefers medical treatment
Family history– Father: hypercholesterolemia,
MI at 64 years
Social history– Smoked 1 pack/day for 25 years, quit
5 years ago – Occasional glass of wine with dinner
(2–3 glasses per week)– Sedentary lifestyle– Tries to adhere to recommended diet
65-year-old African American woman
Aspirin 81 mg
ER metoprolol succinate 50 mg
Atorvastatin 20 mg
Lisinopril 40 mg
Long-acting nitrates Max dose (HA)
Amlodipine 10 mg
Current medications (qd)
2
Physical exam & laboratory values (on medication)
65-year-old African American woman
Physical exam Laboratory ValuesBP (mm Hg) 138/82 LDL-C (mg/dL) 76HR (bpm) 78 HDL-C (mg/dL) 46
HT (in) 68 Total-C (mg/dL) 146WT (lb) 184 TG (mg/dL) 120BMI (kg/m2) 28 Creatinine (mg/dL) 1.1
Fasting glucose (mg/dL) 103A1C (%) 5.8
Other observations:No evidence of heart failure in physical exam
ECG: Sinus rhythm, rate 70 bpm, Q waves in inferior leads,Stress test confirms myocardial ischemia
ECHO: LVEF 48%Chest X-ray: Normal
ARS Question #1
After emphasizing diet and exercise (weight loss), what would you do about her medications?
1) Make no Rx changes
2) Increase B-blocker dose (to 100 mg/day)
3) Increase statin dose (to 40 mg/day)
4) Add ranolazine 500 mg bid
?
Symptoms occur at end of ischemic cascade
Cohn PF et al. Circulation. 2003;108:1263-77.Adapted from Kern MJ. In: Braunwald’s Heart Disease. 7th ed.
• Approximately ½ of patients with angina also experience episodes of asymptomatic (silent) ischemia
• Many episodes of ischemia never become painful
Magnitude of ischemia
Duration of ischemia (sec)
↓ Relaxation (diastolic
dysfunction)
Systolicdysfunction
↓ Filling
↓ ST
AnginaAbnormalities evolving during ischemia
0 30
Management of Chronic CAD: Objectives
Reduce ischemia and relieve anginal symptoms
Improve “quality” of life
Prevent MI and death
Modify natural history of disease(Improve “quantity” of life)
Gibbons RJ, et al. Circulation. 2003;107:149-158.http://acc.org/qualityandscience/clinical/guidelines/stable/stable_clean.pdf.
Chronic stable angina: PharmacotherapyACC/AHA guidelines
Gibbons RJ et al. ACC/AHA 2002 guidelines.www.acc.org/clinical/guidelines/stable/stable.pdf.
Grundy SM et al. Circulation. 2004;110:227-39.*Optional goal of <70 mg/dL in patients at very high risk (ATP III Update)
II IIaIIa IIbIIb IIIIIIAspirin
β-blockers in patients with prior MI
β-blockers in patients without prior MI
Lipid-lowering therapy in patients with suspected CAD and LDL-C >130 mg/dL(target LDL-C <100 mg/dL*)
ACEI in all patients with CAD who have diabetes and/or LV systolic dysfunction
2007 Chronic Angina Recommendations Smoking Cessation
• Assess tobacco use. • Strongly encourage patient and family to stop smoking.
• Avoidance of exposure to environmental tobacco smoke at work and home.
• Follow‐up referral to special programs and/or pharmacotherapy recommended as appropriate. (Ask, Advise, Assess, Assist, Arrange).
Fraker et al. J Am Coll Cardiol. 2007;50 (23): 2264 -74
3
2007 Chronic Angina Recommendations Weight Management/Physical Activity
• Recommend weight management and physical activity as appropriate.
• The patient’s risk should be assessed with a physical activity history. Where appropriate, an exercise test is useful to guide the exercise prescription.
• Encourage minimum of 30 to 60 minutes of activity, preferably daily, or at least 3 or 4 times weekly supplemented by an increase in daily lifestyle activities.
• Medically supervised programs (cardiac rehabilitation) are recommended for at‐risk patients (e.g., recent acute coronary syndrome or revascularization, heart failure).
• Expanding physical activity to include resistance training on 2 days per week may be reasonable
Fraker et al. J Am Coll Cardiol. 2007;50 (23): 2264 -74
Exercise vs PCI in low-risk CAD
N = 101 men with CCS class I–III angina*
20 min bicycle ergometry daily PCI
Assessed at 12 months
Lower resting HR (P < 0.01)
Greater improvement in maximal O
2uptake (P < 0.001)
Hambrecht R et al. Circulation. 2004;109:1371-8.
Fewer rehospitalizations
Lower cost
Exercise vs PCI
*>80% had 1- or 2-vessel disease
2007 Chronic Angina Recommendations Antiplatelet Agents/Anticoagulants
• Aspirin should be started at 75 to 162 mg daily and continued indefinitely in all patients unless contraindicated.
• Clopidogrel after PCI• Warfarin to international normalized ratio (INR) 2.0 to 3.0 in post‐MI patients when clinically indicated or for those not able to take aspirin or clopidogrel.
• Use of warfarin in conjunction with aspirin and/or clopidogrel is associated with an increased risk of bleeding and should be monitored closely
Fraker et al. J Am Coll Cardiol. 2007;50 (23): 2264 -74
2007 Chronic Angina RecommendationsACE Inhibition
• ACE inhibitors should be started and continued indefinitely in all patients with left ventricular ejection fraction less than or equal to 40% and in those with hypertension, diabetes, or chronic kidney disease unless contraindicated.
• Use as needed to manage blood pressure or symptoms in all other patients.
• It is reasonable to use ACE inhibitors among lower‐risk patients with mildly reduced or normal left ventricular ejection fraction in whom cardiovascular risk factors are well controlled and revascularization has been performed .
Fraker et al. J Am Coll Cardiol. 2007;50 (23): 2264 -74
2007 Chronic Angina RecommendationsRenin‐Angiotensin‐Aldosterone System Blockers
• Angiotensin receptor blockers are recommended for patients who have hypertension, have indications for but are intolerant of ACE inhibitors, have heart failure, or have had a myocardial infarction with left ventricular ejection fraction less than or equal to 40%. Angiotensin receptor blockers may be considered in combination with ACE inhibitors for heart failure due to left ventricular systolic dysfunction.
• Aldosterone blockade is recommended for use in post‐MI patients without significant renal dysfunction or hyperkalemiawho are already receiving therapeutic doses of an ACE inhibitor and a beta blocker, have a left ventricular ejection fraction less than or equal to 40%, and have either diabetes or heart failure
Fraker et al. J Am Coll Cardiol. 2007;50 (23): 2264 -74
2007 Chronic Angina Recommendations Beta Blockers
• Use as needed to manage angina, rhythm, or blood pressure.
• It is beneficial to start and continue beta‐blocker therapy indefinitely in all patients who have had MI, acute coronary syndrome, or left ventricular dysfunction with or without heart failure symptoms, unless contraindicated.
Fraker et al. J Am Coll Cardiol. 2007;50 (23): 2264 -74
4
2007 Chronic Angina Recommendations Blood Pressure Control
• Lifestyle modification (weight loss, physical activity, alcohol moderation, moderate sodium restriction, and emphasis on fruits,vegetables, and low‐fat dairy products) in all patients with blood pressure greater than or equal to 130/80 mm Hg.
• Blood pressure control according to Joint National Conference VII guidelines is recommended (i.e., blood pressure less than 140/90 mm Hg or less than 130/80 mm Hg for patients with diabetes or chronic kidney disease).
• For hypertensive patients with coronary artery disease, it is useful to add blood pressure medication as tolerated, treating initially with beta blockers and/or ACE inhibitors, with addition of other drugs as needed to achieve target blood pressure.
Fraker et al. J Am Coll Cardiol. 2007;50 (23): 2264 -74
2007 Chronic Angina Recommendations Lipid Management
• LDL‐C should be <100 mg/dL and reduction of LDL‐C to <70 mg/dL . Use of high‐dose statin therapy is reasonable.
• Start dietary therapy in all patients (less than 7% saturated fat and less than 200 mg per dL cholesterol) and promote physical activity and weight management. Encourage increased consumption of omega‐3 fatty acids.
• Consider omega‐3 fatty acids as adjunct for high TG. For all patients, encouraging consumption of omega‐3 fatty acids in the form of fish, or in capsule form (1 g per day) for risk reduction may be reasonable. For treatment of elevated TG, higher doses are usually necessary for risk reduction.
Fraker et al. J Am Coll Cardiol. 2007;50 (23): 2264 -74
2007 Chronic Angina RecommendationsDiabetes Management
Diabetes management should include lifestyle and pharmacotherapy measures to achieve a near‐normal
HbA1c.
Fraker et al. J Am Coll Cardiol. 2007;50 (23): 2264 -74
Patient Assessment at Every Visit
• Change in level of physical activity?
• Change in frequency/severity of symptoms?
• Medication compliance/tolerance
• Progress in lifestyle changes?
• New co‐morbid conditions or drug Rx?
Anti-Ischemic Strategies in Chronic Symptomatic CAD
PCI Revascularization CABG
Recurrent ischemia
Angiogenic therapy TMR OTHER MEASURES ECP SCS
↑ antianginal drug therapy(up-titrate/add new agents)
Repeat revascularization (if possible)
EECP, external counterpulsation; SCS spinal cord stimulation; TMR, transmyocardial revascularization.Gibbons RJ, et al. J Am Coll Cardiol. 2003;41:159-168.Available at : http://www.acc.org//qualityandscience/clinical/guidelines/stable/stable_clean.pdf.
Initial Medical Therapy
Persistent Angina or High Risk Features
2002 ACC/AHA Class I Revascularization Recommendations
in Chronic AnginaClass I1. CABG for patients with significant LMD (Level of Evidence: A)2. CABG for patients with 3-vessel disease The survival benefit is greater in
patients with abnormal LVEF ≤ 0.5 (Level of Evidence: A)3. CABG for patients with 2-vessel disease with significant proximal LAD
CAD and either abnormal LVEF ≤ 0.5 or demonstrable ischemia on non-invasive testing (Level of Evidence: A)
4. PCI for patients with 2- or 3-vessel disease with significant proximal LAD CAD, who have anatomy suitable for catheter-based therapy and normal LV function and who do not have treated diabetes (Level of Evidence: B)
LMD, left main coronary disease; LAD CAD, left anterior descending coronary artery disease; SCD, sudden cardiac death; VT, ventricular tachycardia.Gibbons RJ, et al. J Am Coll Cardiol. 2003;41:159-168.Available at : http://www.acc.org//qualityandscience/clinical/guidelines/stable/stable_clean.pdf.
5
2002 ACC/AHA Class I Revascularization Recommendations
in Chronic Angina, cont’dClass I, cont’d5. CABG for patients with 1- or 2-vessel CAD without significant proximal
LAD CAD who have survived SCD or sustained VT (Level of Evidence: C)
6. 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 (Level of Evidence: C)
7. PCI or CABG for patients who have not been successfully treated by medical therapy (see text) and can undergo revascularization with acceptable risk (Level of Evidence: B)
8. PCI or CABG for patients with 1- or 2-vessel CAD without significant proximal LAD CAD but with a large area of viable myocardium and high-risk criteria on noninvasive testing (Level of Evidence: B)
LMD, left main coronary disease; LAD CAD, left anterior descending coronary artery disease; SCD, sudden cardiac death; VT, ventricular tachycardia.Gibbons RJ, et al. J Am Coll Cardiol. 2003;41:159-168.Available at : http://www.acc.org//qualityandscience/clinical/guidelines/stable/stable_clean.pdf.
Major cardiac events occur in non-target areas following successful PCI
Hazardrate (%)
Cutlip DE et al. Circulation. 2004;110:1226-30.
Substantial number of cardiac events could be preventedif non-obstructive, high-risk lesions were identified
Target lesion event
Non-target lesion event
0
5
10
15
20
1 2 3Year
4 5
35
30
25
20
15
10
5
06 12 18 24 30 36 42 48 54 60
Cum
ulat
ive
Prob
abili
ty o
fC
umul
ativ
e Pr
obab
ility
of
Car
diov
ascu
lar E
vent
s (%
)C
ardi
ovas
cula
r Eve
nts
(%)
MonthsMonths
PP=0.001=0.001
Poor Rx(n=75)
Moderate Rx(n=123)
Maximal Rx(n=90)
Sdringola S, et al. J Am Coll Cardiol. 2003;41:263-272.
Intensity of Medical Therapyand Outcomes
0
Rx, treatment.
Meta-analysis of 11 randomized trials; N=2950
Chronic Stable CAD: PCI vsConservative Medical Management
Death
Cardiac death or MI
Nonfatal MI
CABG
PCI
Katritsis DG, et al. Circulation. 2005;111:2906-2912.
0 1 2
P value
0.68
0.28
0.12
0.82
0.34
Risk ratio (95% Cl)
Favors PCI Favors medical management
CI, confidence interval; CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention
COURAGE: Background and rationale
• Elective PCI procedures are common in the US (~ 85% of patients)
• PCI decreases angina frequency but long-term prognostic effects on CV events are not known
• Antianginal agents also provide symptom relief
• ACEIs, ASA, β-blockers, and statins have been shown to prevent MI and death
Boden WE et al. N Engl J Med. 2007;356.Boden WE et al. Am Heart J. 2006;151:1173-9.
COURAGE was designed to evaluate whether PCI plus optimal medical therapy reduces risk of major CV events compared with
optimal medical therapy alone in stable CAD patients
In patients with stable CAD
Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation
COURAGE: Study design
Boden WE et al. N Engl J Med. 2007;356.
Optimal medical therapy* + PCI (n = 1149)
Optimal medical therapy(n = 1138)
AHA/ACC Class I/II indications for PCI, suitable coronary artery anatomyand
≥70% stenosis in ≥1 proximal epicardial vessel + objective evidence of ischemia or
≥80% stenosis + class III angina without provocation testing
Primary outcome:All-cause mortality, nonfatal MI
Follow-up: Median 4.6 years
Randomized
*Intensive pharmacologic therapy + lifestyle intervention
6
COURAGE: Treatment effect on primary outcome
HR 1.05*(0.87-1.27)P = 0.62
Boden WE et al. N Engl J Med. 2007;356.
All-cause death, MI
*Unadjusted
Medical therapy PCI + medical therapy
No. at riskMedical therapy 1138 1017 959 834 638 408 192 30PCI 1149 1013 952 833 637 417 200 35
Survival free of primaryoutcome
0 2 4 70
0.5
0.6
0.7
0.8
1.0
0.9
Years6531
COURAGE: Summary and implications
• When added to optimal medical therapy, PCI ↓angina – PCI did not reduce long-term rates of death, MI, or hospitalization for
ACS
• Findings reinforce existing clinical practice guidelines– PCI can be safely deferred if intensive medical therapy is instituted
and maintained
• Initial management approach for many patients includes:– Lifestyle modification + pharmacologic therapy
(diet, ↑physical activity, antiplatelet, antianginal, ↓BP, ↓lipids, and ↓glucose)
– Some patients (~1/3) may require eventual revascularization
Boden WE et al. N Engl J Med. 2007;356.
In patients with stable CAD
Persistent ischemia (angina) despite PCI
27.9 29.9
60.9
78.6
0
20
40
60
80
100
Nitrates CCBs β-blockers ≥1antianginal
Antianginal therapy
Patients (%)
Despite adjunctive antianginal therapy,
26% of patients reported recent
angina
Holubkov R et al. Am Heart J. 2002;144:826-33.
N = 1620 consecutive NHLBI Dynamic Registry patients; 1 year post-PCI
Persistent ischemia (angina) despite optimal revascularization
78.989.5
21.1
41.5
19.1
38.4
0
20
40
60
80
100
Stenting group* Surgery group*
Patients(%)
Free of anginaFree of antianginal medicationFree of angina and antianginal medication
Serruys PW et al. N Engl J Med. 2001;344:1117-24.
*1 year after optimal revascularization (stenting or surgery) for ischemia relief (not to prolong survival)
~60% to 80% taking antianginalmedication
~10 to 20% had angina
Arterial Revascularization Therapies Study
…the goal of treatment should be complete, or nearly complete, elimination of anginal chest pain and return to normal activities and a functional capacity of CCS class I angina…with minimal side effects of therapy.
Gibbons RJ, et al. J Am Coll Cardiol. 2003;41:159-168. Available at : http://www.acc.org//qualityandscience/clinical/guidelines/stable/stable_clean.pdf.
ACC/AHA Angina Guidelines Recommend Complete Relief Without Side Effects
Ischemia is related to myocardial O2 supply and demand
Adapted from Morrow DA et al. In: Braunwald’s Heart Disease. 7th ed.
Oxygen demand
Oxygen supply
Heart rate
Contractility
Wall tension
Coronary blood flow
Collaterals
AoP – LVED gradientSystolic
pressure Volume
LVEDP Ao dias. pressureIschemia
Diastolic time
Spasm/ autoreg.
7
Older antianginal drugs: Pathophysiologic effects
β-blockers
DHP CCBs
Non-DHP CCBs
Long-acting nitrates
Drug classCoronary
blood flowArterial
pressureVenousreturn
Myocardialcontractility
Heartrate
CCB = calcium channel blockerDHP = dihydropyridine*Except amlodipine
Boden WE et al. Clin Cardiol. 2001;24:73-9.Gibbons RJ et al. ACC/AHA 2002 guidelines.
www.acc.org/clinical/guidelines/stable/stable.pdfKerins DM et al. In: Goodman and Gilman’s
The Pharmacological Basis of Therapeutics. 10th ed.
O2 DemandO2 Supply
/
*
Older antianginal drugs: Clinical conditions that may limit use
Drug Class
β-blockers Nitrates Calcium channel blockers
• AsthmaSevere bradycardiaAV blockSevere depressionDiabetesRaynaud’s syndromePeripheral vascular
diseaseSick sinus syndrome
Severe aortic stenosisHypertrophic
obstructive cardiomyopathy
Erectile dysfunction‡
AV block*Bradycardia*Heart failure*Hypertrophic
obstructive cardiomyopathy†
Left ventricular dysfunction*
Sinus node dysfunction*
*Nondihydropyridine CCBs†Dihydropyridine CCBs‡Treated with PDE5 inhibitors
Gibbons RJ et al. www.acc.org/clinical/guidelines/stable/stable.pdf.
“Unmet needs” in treating persistent angina
• Despite medical therapy and/or revascularization, some patients continue to experience angina
• Current treatment options for persistent angina are limited
• Newer treatment approaches are now available
• How best to manage symptomatic patients?
Late Na+ current inhibition: Ranolazine
Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13.Belardinelli L et al. Eur Heart J Suppl. 2004;(6 suppl I):I3-7.
Myocardial ischemia
↑ Late INa
Na+ Overload
Ca2+ Overload
Mechanical dysfunction↑ LV diastolic tension
↓ Contractility
Electrical dysfunctionArrhythmias
Ranolazine
Ranolazine: Pathophysiologic effects vs older antianginals
—†————Late Na+ current inhibitors(ranolazine)
—↓↓↑ / —↑Long-acting nitrates
↓—↓↓↑Non-DHP CCBs
↓—↓↑*↑DHP CCBs
↓—↓↓—β-blockers
Myocardial contractility
Venous return
Arterial pressureHeart rate
Coronary blood flowDrug class
O2 DemandO2 Supply
*Except amlodipine†Ranolazine: No direct effect butmay prevent ischemia-related decline
Boden WE et al. Clin Cardiol. 2001;24:73-9.Gibbons RJ et al. ACC/AHA 2002 guidelines.
www.acc.org/clinical/guidelines/stable/stable.pdfKerins DM et al. In: Goodman and Gilman’s
The Pharmacological Basis of Therapeutics. 10th ed.
CARISA: Ranolazine reduces angina frequency
4.6
3.3
4.3
2.5
4.5
2.1
0
1
2
3
4
5
Baseline Week 12
Chaitman BR et al. JAMA. 2004;291:309-16.
P < 0.001
P = 0.006
Anginalepisodes
perweek
Placebo Ranolazine SR750 mg bid
Ranolazine SR1000 mg bid
Background CCB or β-blocker plus nitrates prnN=823
8
ERICA: Ranolazine reduces angina frequency and nitrate consumptionN = 565
Nitroglycerin useAnginal attacks
P = 0.028P = 0.014
Stone PH et al. Circulation. 2005;112(suppl II):II-748-9.
0
1
2
3
4
5
6
Baseline Week 7 Baseline Week 7
Meannumber
perweek
Placebo Ranolazine SR 1000 mg bid
Components of Primary EndpointComponents of Primary Endpoint
CV Death or MI (%) Recurrent Ischemia (%)
Days from Randomization
Ranolazine 13.9%*(N=3,279)
Placebo 16.1%*(N=3,281)
0 180 360 540
HR 0.87 (95% CI 0.76 to 0.99)P =0.030
0
5
10
15
20
0
5
10
15
0 180 360 540
Ranolazine 10.4%*
Placebo 10.5%*
HR 0.99 (95% CI 0.85 to 1.15)P =0.87
20
Days from Randomization
*KM Cumulative Incidence (%) at 12 monthsMorrow DA et al. JAMA 2007; 297: 1775-83
Assessment of AntiAssessment of Anti--anginalanginal EffectsEffects
RANOLAZINE(N=3,279)
PLACEBO(N=3,281)
*KM Cumulative Incidence at 12 months
5.9
4.2
0
1
2
3
4
5
6
7
8
Worsening Angina (%)*
23% ↓P = 0.023
1310.6
0
2
4
6
8
10
12
14
16
18
Antianginal Increase (%)*
20% ↓P = 0.003
% %
Morrow DA et al. JAMA 2007; 297: 1775-83
Current Indications forRanolazine Extended Release
Indicated for the treatment of chronic angina
May be used with with beta-blockers, nitrates, calcium channel blockers, anti-platelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensinreceptor blockers.
Initiate therapy at 500 mg bid and increase to 1000 mg bid (maximum recommended), as needed, based on clinical symptoms
Ranolazine prescribing information. Available at http://www.fda.gov/cder/foi/label/2008/021526s004lbl.pdf
Ranolazine Safety and Tolerability
Most adverse events were well-tolerated, with <5% of patients discontinuing treatment due to an adverse eventMost common adverse events that led to discontinuation were dizziness (1.3%), nausea (1.0%), asthenia, constipation, and headache (each about 0.5%)Ranolazine 500 to 1000 mg bid associated with an average ~5 milliseconds increase in the QTc. Clinical experience has not shown an increased risk of proarrhythmia or sudden death
Chaitman BR, et al. JAMA. 2004;291:309-316. Stone PH, et al. J Am Coll Cardiol. 2006;48:566-575.Chaitman BR. Circulation. 2006;113:2462-2472.
Ranolazine Drug Interactions
Inhibitors of CYP3A increase ranolazine plasma levels and QTc prolongation:
Limit maximum dose to 500 mg twice daily
Ketoconazole and other azole antifungals
Diltiazem
Verapamil
Macrolide antibiotics
HIV protease inhibitors
Grapefruit juice or grapefruit-containing products
Ranolazine prescribing information. Available at http://www.fda.gov/cder/foi/label/2008/021526s004lbl.pdf
9
Optimal Medical Management
Antiplatelet therapy– Aspirin– Clopidogrel (post-ACS/PCI)
ACEI/ARB– LV dysfunction– LVH– CKD (eGFR<60 mL/min)
StatinGlycemic control (microvascular)Blood pressure controlBeta-blockerNitratesRanolazine
↓ MI
↓ Heart Failure
↓ Death
↓ Symptoms
↑ Exercise
ACEI, angiotensin-converting enzyme inhibitor; CKD, chronic kidney disease; eGRF, estimated glomerular filtration rate; LVH, left ventricular hypertrophy.
Anti-Ischemic Strategies in Chronic Symptomatic CAD
PCI Revascularization CABG
Recurrent ischemia
Angiogenic therapy TMR OTHER MEASURES ECP SCS
↑ antianginal drug therapy(up-titrate/add new agents)
Repeat revascularization (if possible)
EECP, external counterpulsation; SCS spinal cord stimulation; TMR, transmyocardial revascularization.Gibbons RJ, et al. J Am Coll Cardiol. 2003;41:159-168.Available at : http://www.acc.org//qualityandscience/clinical/guidelines/stable/stable_clean.pdf.
Initial Medical Therapy
Persistent Angina or High Risk Features
EECP improves angina class
73.4
39.5
22.0
01020304050607080
≥ 1 classes ≥ 2 classes ≥3 classes
Improvement in CCS angina class
Patients(%)
Lawson WE et al. Cardiology. 2000;94:31-5.
N = 2289 consecutive EECP Clinical Consortium patients
EECP = enhanced external counterpulsation
Case Study:65-year-old African American woman with persistent angina
65-year-old African American woman
New patient
Semi-retired real estate agent, works periodically
Chest pain and short of breath during modest activity for past 6 months.
Presenting complaintLess obstructive CAD: Women vs men
0
20
40
60
80
100
<40 40-49 50-59 60-69 70-79 >79
Patients with >50% stenosis
(%)
Patients undergoing elective diagnostic angiography for angina
Women Men
ACC-National Cardiovascular Data Registry™. J Am Coll Cardiol. 2006.
10
Higher incidence of major CV events in women
0
2
4
6
8
10
12
14
Death Nonfatal MI HF Unstableangina
Emergencyrevasc
Overall angina population
Angina with angiographic CAD
Women
Women
Men
Men
Euro Heart Survey of Stable Angina; n = 1547 women, n = 2478 men
Daly C et al. Circulation. 2006;113:490-8.
Incidence (%)
CRUSADE: Gender and discharge medications
93 91
60
7769
95 93
63
8475
0
20
40
60
80
100
Aspirin β-blocker ACEI Statin Clopidogrel
Discharge medications
N = 35,897 patients with UA/NSTEMI
CRUSADE. www.crusadeqi.com
Patients (%)
MenWomen
Oct 2004–Sept 2005P values not reported
History
65-year-old African American woman
Medical history– Hypertension and
hypercholesterolemia– Post-MI 2 years ago:
• LVEF by ECHO 48%• Angiogram revealed triple-vessel
disease with complex lesions not amenable to PCI
– Triple-vessel CABG (mammaryto LAD). Chest pain recurred 18 months after.
• Repeat CABG ruled out from angiogram .
• Prefers medical treatment
Family history– Father: hypercholesterolemia,
MI at 64 years
Social history– Smoked 1 pack/day for 25 years, quit
5 years ago – Occasional glass of wine with dinner
(2–3 glasses per week)– Sedentary lifestyle– Tries to adhere to recommended diet
65-year-old African American woman
Aspirin 81 mg
ER metoprolol succinate 50 mg
Atorvastatin 20 mg
Lisinopril 40 mg
Long-acting nitrates Max dose (HA)
Amlodipine 10 mg
Current medications (qd)
Physical exam & laboratory values (on medication)
65-year-old African American woman
Physical exam Laboratory ValuesBP (mm Hg) 138/82 LDL-C (mg/dL) 76HR (bpm) 78 HDL-C (mg/dL) 46
HT (in) 68 Total-C (mg/dL) 146WT (lb) 184 TG (mg/dL) 120BMI (kg/m2) 28 Creatinine (mg/dL) 1.1
Fasting glucose (mg/dL) 103A1C (%) 5.8
Other observations:No evidence of heart failure in physical exam
ECG: Sinus rhythm, rate 70 bpm, Q waves in inferior leads,Stress test confirms myocardial ischemia
ECHO: LVEF 48%Chest X-ray: Normal
ARS Question #2
After emphasizing diet and exercise (weight loss), what would you do about her medications?
1) Make no Rx changes
2) Increase B-blocker dose (to 100 mg/day)
3) Increase statin dose (to 40 mg/day)
4) Add ranolazine 500 mg bid
5) Other
?
11
ARS Question #3• B‐blocker dose is increased to 100 mg/day and patient returns in 4 weeks complaining of fatigue (heart rate=60 bpm; BP 128/78 mmHg) No improvement in symptoms.
Would you now:
1) Make no further Rx changes
2) Refer for further evaluation
3) Start ranolazine 500 mg bid
4) Recommend EECP or other
? Summary
• Chronic angina continues to impose a high socioeconomic burden
• Renewed interest in the role of optimal medical therapy vs PCI (COURAGE)
• Contemporary medical management:– Aggressive treatment of multiple risk factors (ABC’s)
– Multifactorial treatment of symptoms involving both dosage up‐titration (BB, CCBs and nitrates) and adding additional agents as necessary to improve the quality of life
Recommended