1. Treatment of Chronic Angina
How to control difficult angina
Anthony Haney MD, FACC

2. Disclosure Speaker’s bureau - Gilead Sciences (ranolazine/Ranexa)
Discussing non-FDA approved therapies

4. 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
Concepts discussed may or may not apply to unstable angina
References
Chestnut LG, Keller LR, Lambert WE, et al. Measuring heart patients' willingness to pay for changes in angina symptoms. Med Decis Making. 1996;16:65-77.
Williams SV, Fihn SD, Gibbons RJ. Guidelines for the management of patients with chronic stable angina: diagnosis and risk stratification. Ann Intern Med. 2001;135:
Chestnut LG, et al. Med Decis Making. 1996;16:65-77.
Williams SV, et al. Ann Intern Med. 2001;135:

5. 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)

6. Chronic Angina Is Prevalent in the United States
~10 million Americans have angina pectoris
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)
500,000
320,000
180,000
As pts undergo more advanced revascularization procedures, live longer and develop disease not amenable to PCI/redo CABG
References
Lloyd-Jones D, Adams R, Carnethon M, et al. Heart Disease and Stroke Statistics 2009 Update: A report from the American Heart Association Statistics Committee and Stroke Statistics Sub-Committee. Circulation. 2009;119:e21-e181.
Pepine CJ, Abrams J, Marks RG, et al. Characteristics of a contemporary population with angina pectoris. TIDES Investigators. Am J Cardiol. 1994;74:
Men
Women
Total
American Heart Association. Heart Disease and Stroke Statistics, 2009 Update. Pepine CJ, et al. Am J Card. 1994;74:

7. 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
Gender
Typical Angina Symptoms
Atypical Angina Symptoms
Male (n = 2249)
55%*
34%*
Female (n = 976)
28%
53%
References
Alexander KP, Shaw LJ, DeLong ER, et al. Value of exercise treadmill testing in women. J Am Coll Cardiol. 1998;32:
Ellis K, Kapadia SR. Stable angina. In: Griffin BP, Topol EJ, eds. Manual of Cardiovascular Medicine. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:74-75.
McSweeney JC, Cody M, O’Sullivan P, Elberson K, Moser DK, Garvin BJ. Women’s early warning symptoms of acute myocardial infarction. Circulation. 2003;108:
*p < 0.05 for comparison across gender
Alexander KP, et al. J Am Coll Cardiol. 1998;32: Ellis K, et al. Manual of Cardiovascular Medicine. 2nd ed McSweeney JC, et al. Circulation. 2003;108:

8. Differential Diagnosis of noncardiac chest pain

9. Pain Symptoms Occur at the End of the Ischemic Cascade
ECG 
↓Diastolic Filling
ST alterations
↓ Contraction
Magnitude of Ischemia
Systolic Dysfunction
↓ Relaxation
Reference
Kern MJ. Atherosclerotic cardiovascular disease. In: Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 7th ed. Philadelphia, PA: Elsevier Saunders; 2005:
Diastolic Dysfunction
Biochemical
Alterations
Stress Duration
Adapted from Kern MJ. In: Braunwald’s Heart Disease. 7th ed

14. Symptoms of Angina Persist Despite OMT ± PCI
The COURAGE Study (N = 2287)
p = NS
PCI + OMT
One-quarter to one-third of patients had persistent angina/ischemia despite OMT ± PCI
OMT
p < 0.001
Continuing Angina (%)
p = 0.02
p = NS
In the COURAGE study, 2287 patients with objective evidence of myocardial ischemia and significant CAD were randomized to an initial treatment strategy of PCI plus OMT vs OMT alone.
Patients with stable CAD were included in the study. Entry criteria included stenosis of more than 70% in at least one proximal epicardial coronary artery with objective evidence of MI or stenosis of at least 80% in at least one coronary artery and classic angina without provocative testing.
Exclusion criteria included persistent CCS class IV angina, a markedly positive stress test (substantial ST-segment depression or hypotensive response during stage 1 of the Bruce protocol), refractory heart failure or cardiogenic shock, an ejection fraction of less than 30%, revascularization within the previous 6 months, and coronary anatomy not suitable for PCI.
Intensive, guideline-driven medical therapy (antiplatelets, statins, ACE inhibitors/ARBs, beta-blockers, CCBs, nitrates) and lifestyle intervention (smoking cessation, exercise, nutrition counseling, weight control) in both groups (OMT)
The primary outcome was a composite of death and myocardial infarction.
Baseline clinical characteristics were similar in the groups assigned to PCI plus OMT and the group of patients assigned to OMT.
All of the patients received aspirin, and those who were undergoing PCI also received clopidogrel in accordance with treatment guidelines. Anti-ischemic therapy included long-acting metoprolol, amlodipine, and isosorbide mononitrate, alone or in combination, together with simvastatin and either lisinopril or losartan for secondary prevention.
Median follow-up was 4.6 years (range 2.5 to 7 years).
Reference
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:
Points from previous slide on COURAGE study design
2287 patients randomized to PCI + OMT vs OMT alone
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:

15. Physiologic Effects of Antianginal Treatments
O2 Supply
O2 Demand
Coronary
blood flow
Heart
rate
Arterial
pressure
Venous
return
Myocardial
contractility
Therapy
Beta-blockers
DHP CCBs
Non-DHP CCBs
Long-acting nitrates
Ranolazine
Revascularization 1 /
References
Bagger JP, Bøtker HE, Thomassen A, Toftegaard T, Nielsen TT. Effects of Ranolazine on Ischemic Threshold, Coronary Sinus Blood Flow, and Myocardial Metabolism in Coronary Artery Disease. Cardiovasc Drugs Ther. 1997;11(3):
Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina--summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). 2003;41:
Kerins DM, Robertson RM, Robertson D. Drugs used for the treatment of myocardial ischemia. 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;
Naik H, et al. Ischemic heart disease. In: Lilly L, ed. Pathophysiology of Heart Disease. 4th ed. Baltimore, MD: Lippincott, Williams & Wilkins; 2007: / 2 2 2 2
1Less reflex tachycardia with amlodipine. 2Specific data not available. CCB = calcium channel blocker; DHP = dihydropyridine
Bagger JP, et al. Cardiovasc Drugs Ther. 1997;11(3): Gibbons RJ, et al. ACC/AHA 2002 Chronic Angina Guidelines. 2003;41: 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: Lilly L, ed. Pathophysiology of Heart Disease. 4th ed. Baltimore, MD: Lippincott, Williams & Wilkins; 2007: Ranexa® (ranolazine extended-release tablets) PI. 3/2009.

16. 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

17. Beta Blocker Issues Rebound angina with withdrawal Adverse effects
Fatigue/Exercise intolerance
Bronchoconstriction
Erectile dysfunction
Central side effects (nightmares/insomnia/depression)

18. 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)

19. 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

20. CCB issues
Do not use short acting nifedipine due to reflex tachycardia/?mortality increase
Adverse effects
Edema
Constipation
Dizziness
GERD

21. 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

22. 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

23. Nitrate Use Sublingual/Spray Isosorbide Dinitrate
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

24. Ranolazine/Ranexa First new antianginal class approved since 1960’s
Late Na+ current inhibitor
Safe & well tolerated
Nausea
Dizziness

25. Ischemic Myocyte Peak Sodium Current‡
Ischemic Myocyte Peak Sodium Current
References
Canty JM Jr. Coronary blood flow and myocardial ischemia. In: Braunwald E, Libby P, Bonow RO, Mann DL, Zipes DP, eds. Heart Disease: A Textbook of Cardiovascular Medicine. 8th ed. Philadelphia, PA: WB Saunders Co; 2008:
Ju YK, Saint DA, Gage PW. Hypoxia increases persistent sodium current in rat ventricular myocytes. J Physiol. 1996;497:
Lazdunski M, Frelin C, Vigne P. The sodium/hydrogen exchange system in cardiac cells: its biochemical and pharmacological properties and its role in regulating internal concentrations of sodium and internal pH. J Mol Cell Cardiol. 1985;17:
Pike MM, Kitakaze M, Marban E. 23Na-NMR measurements of intracellular sodium in intact perfused ferret hearts during ischemia and reperfusion. Am J Physiol. 1990;259:H1767-H1773.
Pike MM, et al. Am J Physiol. 1990;259:H1767-H1773.
Ju YK, et al. J Physiol. 1996;497:
Canty JM Jr. In: Heart Disease: A Textbook of Cardiovascular Medicine. 8th ed. Philadelphia, PA: WB Saunders Co; 2008:
Lazdunski M, et al. J Mol Cell Cardiol. 1985;17:

26. Cardiac Sodium Channel Current‡
Ischemic Myocyte Late Sodium Current
Sodium Current (mV)
Cardiac Sodium Channel Current
References
Canty JM Jr. Coronary blood flow and myocardial ischemia. In: Braunwald E, Libby P, Bonow RO, Mann DL, Zipes DP, eds. Heart Disease: A Textbook of Cardiovascular Medicine. 8th ed. Philadelphia, PA: WB Saunders Co; 2008:
Ju YK, Saint DA, Gage PW. Hypoxia increases persistent sodium current in rat ventricular myocytes. J Physiol. 1996;497:
Lazdunski M, Frelin C, Vigne P. The sodium/hydrogen exchange system in cardiac cells: its biochemical and pharmacological properties and its role in regulating internal concentrations of sodium and internal pH. J Mol Cell Cardiol. 1985;17:
Pike MM, Kitakaze M, Marban E. 23Na-NMR measurements of intracellular sodium in intact perfused ferret hearts during ischemia and reperfusion. Am J Physiol. 1990;259:H1767-H1773.
Increased Late Sodium Current
Pike MM, et al. Am J Physiol. 1990;259:H1767-H1773.
Ju YK, et al. J Physiol. 1996;497:
Canty JM Jr. In: Heart Disease: A Textbook of Cardiovascular Medicine. 8th ed. Philadelphia, PA: WB Saunders Co; 2008:
Lazdunski M, et al. J Mol Cell Cardiol. 1985;17:
Peak Sodium Current (systole)

27. Ischemic Myocyte Late Sodium Current‡
Ischemic Myocyte Late Sodium Current
Sodium-Calcium Exchanger
References
Bers DM, Barry WH, Despa S. Intracellular Na+ regulation in cardiac myocytes. Cardiovasc Res. 2003;57(4):
Bing OHL, Keefe JF, Wolk MJ, et al. Tension prolongation during recovery from myocardial hypoxia. J Clin Invest. 1971;50:
Canty JM Jr. Coronary blood flow and myocardial ischemia. In: Braunwald E, Libby P, Bonow RO, Mann DL, Zipes DP, eds. Heart Disease: A Textbook of Cardiovascular Medicine. 8th ed. Philadelphia, PA: WB Saunders Co; 2008:
Ju YK, Saint DA, Gage PW. Hypoxia increases persistent sodium current in rat ventricular myocytes. J Physiol. 1996;497:
Chaitman BR. Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions. Circulation. 2006;113:
Lazdunski M, Frelin C, Vigne P. The sodium/hydrogen exchange system in cardiac cells: its biochemical and pharmacological properties and its role in regulating internal concentrations of sodium and internal pH. J Mol Cell Cardiol. 1985;17:
Meyer M, Keweloh B, Guth K, et al. Frequency-dependence of myocardial energetics in failing human myocardium as quantified by a new method for the measurement of oxygen consumption in muscle strip preparations. J Mol Cell Cardiol. 1998;30:
Pike MM, Kitakaze M, Marban E. 23Na-NMR measurements of intracellular sodium in intact perfused ferret hearts during ischemia and reperfusion. Am J Physiol. 1990;259:H1767-H1773.
Pike MM, et al. Am J Physiol. 1990;259:H1767-H1773. Ju YK, et al. J Physiol. 1996;497: Lazdunski M, et al. J Mol Cell Cardiol. 1985;17: Meyer M, et al. J Mol Cell Cardiol. 1998;3: Canty JM Jr. In: Heart Disease: A Textbook of Cardiovascular Medicine. 8th ed. Philadelphia, PA: WB Saunders Co; 2008: Bing OHL, et al. J Clin Invest. 1971;50: Bache RJ, et al. Circ Res. 1981;49:

29. 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)
24,000
1000 mg bid Ranexa (n = 238)
20,000
RPP (mm Hg × bpm)
16,000
12,000
References
Ranexa® (ranolazine extended-release tablets) [Prescribing Information]. Palo Alto, CA; 3/2009.
Stone, PH, Chaitman B, Koren A, Crager M. Effects of ranolazine as monotherapy and combination therapy on rate pressure product at rest and during exercise: results from the MARISA and CARISA trials. Circulation. 2006;114:II-715. Abstract 3362.
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 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.

30. 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
Ranexa is primarily metabolized by CYP3A and is a substrate of P-glycoprotein (P-gp). Use of Ranexa is contraindicated in patients who are taking strong CYP3A inhibitors, such as ketoconazole, clarithromycin, or nelfinavir. Use of Ranexa is also contraindicated in patients taking CYP3A inducers, such as rifampin or phenobarbital since these drugs significantly decrease the plasma concentration of Ranexa.
Ranexa is contraindicated in patients with clinically significant hepatic impairment. Plasma concentrations of ranolazine were increased by 30% in patients with mild (Child-Pugh Class A) and by 60% in patients with moderate (Child-Pugh Class B) hepatic impairment. This was not enough to account for the 3-fold increase in QT prolongation seen in patients with mild to severe hepatic impairment.
Reference
Ranexa® (ranolazine extended-release tablets) [Prescribing Information]. Palo Alto, CA; 3/2009.
Please see full prescribing information.
Ranexa® (ranolazine extended-release tablets) PI. 3/2009.

35. 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

37. 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

40. Transmyocardial Laser Revascularization – DIRECT trial

41. 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

43. Medical therapy versus revascularization

49. 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 ( )
P = 0.62
0.6
0.5
0.0 1 2 3 4 5 6 7
Years
Number at Risk
Medical Therapy
PCI

50. 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

54. Medical therapy versus revascularization
How to choose the best strategy

55. 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

56. 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

57. 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

58. Risk of PCI Risk of complication increases as patients age 80’s 60’s
Risk of death % 1%
Risk of renal failure 3.2% 1%
Risk of vascular comp 6.7% 3.3%

59. 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

61. 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

62. 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

63. Novel therapies Ivabradine Rho kinase inhibitor
Inhibits sinus node
Approved in Europe
Rho kinase inhibitor
Relaxes vascular smooth muscle
Testosterone (side effects)
Stem cell therapy
Therapeutic Angiogenesis

64. 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

65. 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