Chronic Stable Angina: Managing Patients With Persistent Symptoms

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.

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Fraker%20TD%20Jr%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Fihn%20SD%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%222002%20Chronic%20Stable%20Angina%20Writing%20Committee%22%5BCorporate%20Author%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22American%20College%20of%20Cardiology%22%5BCorporate%20Author%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus

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.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&term=%22Hilton+TC%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&term=%22Chaitman+BR%22%5BAuthor%5D

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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


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


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)


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


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


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 .


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


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.


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.


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.


2007 Chronic Angina RecommendationsDiabetes Management

Diabetes management should include lifestyle and pharmacotherapy measures to achieve a near‐normal

HbA1c.


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


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


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


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


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


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)


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

Documents

Chronic Stable Angina: Managing Patients With Persistent Symptoms