Treatment of Chronic
Angina
How to control difficult
angina
Anthony Haney MD, FACC
Disclosure
• Speaker’s bureau - Gilead Sciences
(ranolazine/Ranexa)
• Discussing non-FDA approved
therapies
Stable Angina
• Classic angina is substernal chest discomfort
that occurs predictably and is relieved by rest
or nitroglycerin
• Stable pattern for >2 weeks
• Patients with angina may curtail activity to
avoid anginal episodes
• Patients under report symptoms
Chestnut LG, et al. Med Decis Making. 1996;16:65-77.
Williams SV, et al. Ann Intern Med. 2001;135:530-547.
Classification
Class I
Angina with strenuous exertion
(shoveling snow)
Class II
Mild limitation of normal activity
(walking up hill quickly)
Class III
Marked limitation of nl activity
(walking 1-2 blocks)
Class IV
Unable to do physical activity
(may occur even at rest)
Chronic Angina Is
Prevalent in the United States
– 500,000 new cases are
reported annually
• Median angina frequency
is ~2 episodes per patient
per week
– > 18 million episodes
each week or ~30
episodes each second
New Cases of Stable Angina Per Year
(Among Americans ≥ 45 Years of Age)
Incidence
(Number of New Cases)
• ~10 million Americans
have angina pectoris
500,000
320,000
180,000
Men
American Heart Association. Heart Disease and Stroke Statistics, 2009 Update.
Pepine CJ, et al. Am J Card. 1994;74:226-231.
Women
Total
Symptoms Other Than Classic Chest
Pain Are Common in Chronic Angina
• Anginal equivalents are common
– Shortness of breath
– Fatigue
– Weakness
– Lightheadedness
– Diaphoresis
– Nausea
– Indigestion
• In 3225 patients referred to Duke University for cardiac
catheterization, atypical angina symptoms were reported in
both men and women
Typical Angina
Symptoms
Atypical Angina
Symptoms
Male (n = 2249)
55%*
34%*
Female (n = 976)
28%
53%
Gender
*p < 0.05 for comparison across gender
Alexander KP, et al. J Am Coll Cardiol. 1998;32:1657-1664.
Ellis K, et al. Manual of Cardiovascular Medicine. 2nd ed. 2004.
McSweeney JC, et al. Circulation. 2003;108:2619-2623.
Differential Diagnosis of noncardiac
chest pain
Pain Symptoms Occur at the End
of the Ischemic Cascade
Magnitude of Ischemia
PAIN
ECG 
↓Diastolic
Filling
↓ Contraction
↓ Relaxation
Biochemical
Alterations
Systolic
Dysfunction
Diastolic
Dysfunction
Stress Duration
Adapted from Kern MJ. In: Braunwald’s Heart Disease. 7th ed. 2005.
ST alterations
Myocardial Ischemia:
Unbalanced Oxygen Supply and Demand
Coronary
Blood Flow
Contractility
Oxygen
Supply
Oxygen
Demand
Heart Rate
LV Wall Tension
Coronary Perfusion
Pressure
Systolic Volume
Pressure Overload
Coronary
Vascular
Resistance
External
Compression
Intrinsic
Regulation
Ischemia
LV = left ventricular.
Kern MJ. In: Braunwald’s Heart Disease. 7th ed. 2005. Naik H, et al. In: Lilly L, ed.
Pathophysiology of Heart Disease. 4th ed. Baltimore, MD: Lippincott, Williams & Wilkins;
2007:141-167.
Impaired microvascular perfusion in the anginal
syndrome
Diminished microvascular perfusion
0.2
Myocardial
perfusion
index*
P = 0.02
P = 0.002
Endocardium
Epicardium

P < 0.001
P = NS
0.1
0
Control (n = 10)
Rest
Endocardium
Epicardium
Chest pain with
normal coronary angiogram (n = 20)
Adenosine infusion
*Assessed via magnetic resonance imaging
Panting JR et al. N Engl J Med. 2002;346:1948-53.
Angina treatment: Objectives
Reduce ischemia and relieve anginal symptoms
Improve quality of life
Prevent MI and death
Improve quantity of life
Gibbons RJ et al. ACC/AHA 2002 guidelines.
www.acc.org/clinical/guidelines/stable/stable.pdf
Comprehensive management of myocardial ischemia
Symptom
management
Aggressive
risk factor
reduction
Antiplatelet
therapy
Lifestyle
modification
Symptoms of Angina Persist Despite
OMT ± PCI
The COURAGE Study (N = 2287)
100
p = NS
Continuing Angina (%)
88 87
80
60
PCI + OMT
OMT
One-quarter to one-third of
patients had persistent
angina/ischemia despite
OMT ± PCI
p < 0.001
42
40
p = 0.02
34
28
33
p = NS
26 28
20
0
Baseline
1 Year
3 Years
5 Years
Ranexa was approved after the COURAGE trial was initiated, and therefore was not part of the trial.
PCI = percutaneous coronary intervention; OMT = optimal medical therapy; CAD = coronary artery disease.
Boden WE, et al. N Engl J Med. 2007;356:1503-1516.
Physiologic Effects of
Antianginal Treatments
O2 Supply
Therapy
Coronary
blood flow
O2 Demand
Heart
rate
Arterial
pressure
Venous
return
Myocardial
contractility
Beta-blockers
1
DHP CCBs
Non-DHP CCBs
Long-acting nitrates
/
2
Ranolazine
Revascularization
1Less
2
2
2
/
reflex tachycardia with amlodipine. 2Specific data not available. CCB = calcium channel blocker; DHP = dihydropyridine
Bagger JP, et al. Cardiovasc Drugs Ther. 1997;11(3):479-484. Gibbons RJ, et al. ACC/AHA 2002 Chronic Angina Guidelines. 2003;41:159-168. Kerins
DM, et al. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: The
McGraw-Hill Companies; 2001:843-870. Lilly L, ed. Pathophysiology of Heart Disease. 4th ed. Baltimore, MD: Lippincott, Williams & Wilkins;
2007:141-167. Ranexa® (ranolazine extended-release tablets) PI. 3/2009.
Beta Blockers
• Decreases oxygen demand by lowering heart
rate, myocardial contractility and wall stress
• Titrate resting HR to 50-60’s
• Typically use cardioselective (metoprolol or
atenolol)
• Improves mortality in post MI and LV
dysfunction patients
• Dose related effect
Beta Blocker Issues
• Rebound angina with withdrawal
• Adverse effects
– Fatigue/Exercise intolerance
– Bronchoconstriction
– Erectile dysfunction
– Central side effects
(nightmares/insomnia/depression)
Calcium Channel Blockers
• Dihydropyridines (nifedipine, amlodipine)
– Relax vascular smooth muscle/vasodilators
– Reduce coronary resistance/increase coronary
blood flow
• Verapamil
– Negative inotrope/lowers HR
– Lowers blood pressure (less potent vasodilation)
• Diltiazem
– Potent coronary, mild systemic vasodilator
– Lowers HR (less than verapamil)
When to use
Calcium Channel Blockers
• Contraindication or intolerance to beta blockers
• Add if BP above goal
• Ongoing symptoms in spite of BB/NTG
• Combination therapy with BB or NTG is more
effective than either agent alone
• Strongly consider if vasospasm is suspected
CCB issues
• Do not use short acting nifedipine due to reflex
tachycardia/?mortality increase
• Adverse effects
– Edema
– Constipation
– Dizziness
– GERD
Nitrates
• Systemic vasodilation >> coronary vasodilation
• Venodilation reduces preload reducing wall
stress and decreasing oxygen demand
• Arteries with flow-limiting disease are
maximally dilated at rest
• Reduces/reverses coronary vasospasm
• Reduce resistance to coronary blood flow from
epi to endocardium
Nitrate Issues
• Nitrate Tolerance
• Rebound angina
• Headache, flushing, lightheadednesss (elderly)
• Cannot be used with ED drugs
• Less effective in Asians
• Response to NTG is not predictive of CAD
Nitrate Use
•
Sublingual/Spray
–
–
–
•
Acute angina
May be used as prophylaxis
Spray lasts 2-3 years
Isosorbide Dinitrate
–
–
•
Dose 8AM, 1PM, 6PM
Start 10mg and titrate to 40mg
Isosorbide Mononitrate
–
–
•
Dose in AM
Start at 30mg and titrate to 120mg
Nitroglycerin Patch
–
Apply at 8AM and remove 8PM
Ranolazine/Ranexa
•
First new antianginal class approved since
1960’s
•
Late Na+ current inhibitor
•
Safe & well tolerated
– Nausea
– Dizziness
‡
Pike MM, et al. Am J Physiol. 1990;259:H1767-H1773.
Ju YK, et al. J Physiol. 1996;497:337-347.
Canty JM Jr. In: Heart Disease: A Textbook of Cardiovascular
Medicine. 8th ed. Philadelphia, PA: WB Saunders Co; 2008:1167-1168.
Lazdunski M, et al. J Mol Cell Cardiol. 1985;17:1029-1042.
Ischemic Myocyte
Peak Sodium Current
‡
Ischemic Myocyte
Late Sodium Current
Cardiac Sodium
Channel Current
0
Sodium
Current
(mV)
Increased Late
Sodium Current
Pike MM, et al. Am J Physiol. 1990;259:H1767-H1773.
Ju YK, et al. J Physiol. 1996;497:337-347.
Canty JM Jr. In: Heart Disease: A Textbook of Cardiovascular
Medicine. 8th ed. Philadelphia, PA: WB Saunders Co; 2008:1167-1168.
Lazdunski M, et al. J Mol Cell Cardiol. 1985;17:1029-1042.
Peak Sodium Current (systole)
‡
Ischemic Myocyte
Late Sodium Current
Sodium-Calcium Exchanger
Pike MM, et al. Am J Physiol. 1990;259:H1767-H1773. Ju YK, et al. J Physiol. 1996;497:337-347. Lazdunski M, et al. J Mol
Cell Cardiol. 1985;17:1029-1042. Meyer M, et al. J Mol Cell Cardiol. 1998;3:1459-1470. Canty JM Jr. In: Heart Disease: A
Textbook of Cardiovascular Medicine. 8th ed. Philadelphia, PA: WB Saunders Co; 2008:1167-1168. Bing OHL, et al. J
Clin Invest. 1971;50:660-666. Bache RJ, et al. Circ Res. 1981;49:742-750.
Na+/Ca2+ overload and ischemia
Myocardial
ischemia
Intramural small vessel compression
( O2 supply)
 Late Na+ current
 O2 demand
Na+ overload
 Diastolic wall tension (stiffness)
Ca2+ overload
Adapted from Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13.
CARISA
The Anti-ischemic Effects of Ranexa Are
Independent of Hemodynamic Changes
Minimal changes in mean heart rate (< 2 bpm)
and SBP (< 3 mm Hg) were observed in patients
treated with Ranexa in controlled clinical studies
Placebo (n = 244)
1000 mg bid Ranexa (n = 238)
RPP (mm Hg × bpm)
24,000
20,000
16,000
12,000
8,000
Rest
0 min
Stage 0
3 min
Stage 0.5
6 min
Stage 1
9 min
Stage 2
12 min
Stage 3
15 min
Stage 4
18 min
Exercise
The rate pressure product (RPP) data are based on a post hoc analysis of patients in the CARISA trial.
All patients were maintained on either amlodipine, diltiazem, or atenolol.
Please see Important Safety Information on slides 46-50 within this presentation.
bpm = beats per minute; SBP = systolic blood pressure.
Stone PH, et al. Circulation. 2006;114:II-715. Abstract 3362.
Ranexa® (ranolazine extended-release tablets) PI. 3/2009.
Ranexa: Contraindications
Ranexa is contraindicated in patients:
• Taking strong inhibitors of CYP3A, such as
ketoconazole, clarithromycin, or nelfinavir
• Taking inducers of CYP3A, such as rifampin or
phenobarbital
• With clinically significant hepatic impairment
Please see full prescribing information.
Ranexa® (ranolazine extended-release tablets) PI. 3/2009.
Exercise vs PCI in low-risk CAD
N = 101 men with CCS class I–III angina*
PCI
20 min bicycle ergometry daily
Assessed at 12 months
Exercise vs PCI
Lower resting HR (P < 0.01)
Fewer rehospitalizations
Greater improvement in maximal
O2 uptake (P < 0.001)
Lower cost
*>80% had 1- or 2-vessel disease
Hambrecht R et al. Circulation. 2004;109:1371-8.
Enhanced External Counterpulsation
• Increases BP and diastolic augmentation
• Improve coronary collateral flow
• Well tolerated
• Daily treatments for 7 weeks
• Approved only for patients with class III or IV
angina who are not candidates for
revascularization
• Benefits are inconclusive
EECP improves angina class
N = 2289 consecutive EECP Clinical Consortium patients
80
73.4
70
60
50
Patients
(%)
39.5
40
30
22.0
20
10
0
≥1 class
≥2 classes
≥3 classes
Improvement in CCS angina class
EECP = enhanced external counterpulsation
Lawson WE et al. Cardiology. 2000;94:31-5.
Transmyocardial Laser
Revascularization
• Transmural channels created by a laser
• Potential mechanisms
– Angiongenesis
– Denervation
– Remodeling
• Periop complications limit usefulness
• May be combined with CABG
• Initial studies showed promise in reducing
symptoms but likely a large placebo effect
Surgical laser TMR improves angina class
N = 275 with CCS class IV angina
100
87
83
60
Improvement*
(% of patients) 40
P < 0.001
TMR vs medical
(both time points)
78
76
80
32
13
20
0
3
12
Time (months)
TMR
Medical
*Reduction of ≥2 CCS classes
†Due to treatment failure
TMR = transmyocardial revascularization
†
Crossover from medical
Allen KB et al. N Engl J Med. 1999;341:1029-36.
Transmyocardial Laser
Revascularization – DIRECT trial
Spinal cord stimulation
• Suppresses intrinsic cardiac neurons
• Reduces sympathetic activity
• No clinical rebound effect
• Primarily analgesic effect
• SPiRiT trial compared spinal cord stimulation to
TMLR in 60 patients- no significant difference
between the groups in terms of the primary end
point of total exercise time or in other
parameters such as CCS functional class
Medical therapy versus
revascularization
Major benefit of PCI: Angina symptom relief
N = 1020 undergoing elective PCI; 1 year follow-up
80
72
70
60
51
50
Patients
(%)
40
30
20
12
17
19
13
10
0
No change
Angina absent
Seattle Angina Questionnaire
Moderate improvement
Large improvement
Change in QOL score
Angina present
Spertus JA et al. Circulation. 2004;110:3789-94.
Stable CAD: PCI vs conservative medical
management
Meta-analysis of 11 randomized trials; N = 2950
Favors medical
management
Favors PCI
P
Death
0.68
Cardiac death or MI
0.28
Nonfatal MI
0.12
CABG
0.82
PCI
0.34
0
1
2
Risk ratio
(95% Cl)
Katritsis DG et al. Circulation. 2005;111:2906-12.
Survival Free of Death from Any
Cause and Myocardial Infarction
Optimal Medical Therapy (OMT)
1.0
0.9
0.8
PCI + OMT
0.7
Hazard ratio: 1.05
95% CI (0.87-1.27)
P = 0.62
0.6
0.5
0.0
0
1
2
1138
1149
1017
1013
959
952
3
Years
4
5
6
7
192
200
30
35
Number at Risk
Medical Therapy
PCI
834
833
638
637
408
417
Courage Trial Conclusions
• As an initial management strategy in patients
with stable coronary artery disease, PCI did not
reduce the risk of death, MI, or other major
cardiovascular events when added to optimal
medical therapy
• As expected, PCI resulted in better angina relief
during most of the follow-up period, but medical
therapy was also remarkably effective, with no
between–group difference in angina-free status
at 5 years
COURAGE: Lifestyle modification goals
Lifestyle characteristics
Goal
Smoking
Cessation
Total dietary fat
<30% of calories
Saturated fat
<7% of calories
Dietary cholesterol
<200 mg/day
Physical activity
≥30 min moderately intensive
exercise 5 times per week
BMI (kg/m2)
<25 (if baseline 25.0–27.5)
10% relative weight loss
(if baseline BMI >27.5)
Boden WE et al. Am Heart J. 2006.
COURAGE: Medical therapy goals
LDL-C (mg/dL)
60–85
HDL-C (mg/dL)
≥40
Triglycerides (mg/dL)
<150
BP (mm Hg)
<130/85
<130/80 if diabetes or renal
disease present
A1C (%)
<7.0
Boden WE et al. Am Heart J. 2006.
Medical therapy versus
revascularization
How to choose the best
strategy
Stress Testing
• Prognostic/Risk stratification
• Evaluate efficacy of medical therapy
• Identify high risk patients (>3% annual mortality)
– EF <35%
– High risk treadmill score (ekg changes in stage I or II)
– Large reversible perfusion defects (particularly anterior)
– Moderate reversible defects with LV dilatation/dysfunction
– Multiple vascular territories involved
– Transient chamber dilatation during stress testing
Refer for Cath & Revascularization
• Angina that interferes with patient’s lifestyle
despite maximal tolerable medical therapy
(class III or IV)
• Patients with high-risk findings on noninvasive
testing
• Survivors of SCD
• Symptoms/signs of CHF
• Equivocal noninvasive testing
• EF <45% with class I or II angina
Factors which may prevent
Revascularization
• Diffuse CAD/unsuitable anatomy/poor targets
• Prior CABG(s)
• Lack of vascular conduits
• Severely impaired LV function/CHF
• Concurrent disease (chronic kidney disease,
advanced DM, prior CVA, infections, obesity)
• Advanced age especially with comorbidities
Risk of PCI
• Risk of complication increases as patients age
80’s
60’s
Risk of death
3.8%
1%
Risk of renal failure
3.2%
1%
Risk of vascular comp
6.7%
3.3%
Follow up visits
• Change in physical activity
• Change in frequency, severity or pattern of
angina
• Tolerance/compliance with medical regimen
• Risk factor modification
• New or worsened comorbid conditions
Novel therapies
• Inhibition of fatty acid oxidation
– Utilize glucose instead of fatty acids as energy
source
– Increases cardiac metabolic efficiency
• Potassium channel activator (Nicorandil)
– Vasodilator
– Mimics ischemic preconditioning
– Approved in multiple countries
Novel therapies
• Allopurinol (treatment for gout)
– Increased exercise time and time to onset of ST
depression in small study when added to OMT
– Improves endothelium-dependent vasodilation
and reduces oxidative stress
• Endothelin receptor blockers (typically used for
primary pulmonary HTN)
– Vasodilator (coronary)
– No clinical trials yet
Novel therapies
• Ivabradine
– Inhibits sinus node
– Approved in Europe
• Rho kinase inhibitor
– Relaxes vascular smooth muscle
• Testosterone (side effects)
• Stem cell therapy
• Therapeutic Angiogenesis
Summary
• Angina is not always chest pain
• Angina is caused by a problem with oxygen
demand and/or supply
• Treatment of angina includes aggressive risk
factor modification to prevent progression of
disease
• Choice of antianginals should consider
comorbidities and side effects
• Antianginal med benefits are additive
Summary
• Antianginal meds/dosages are often not
optimized for maximal effect
• Several nonRx options are available and
effective
• Revascularization is effective at relieving angina
quickly
• Revascularization does not reduce risk of
MI/death in low risk patients
• All patients with angina need risk stratification
• Goal = elimination of angina and return to
normal activity