Antianginal Treatment

1. Anti-anginal Treatments
Dr. Htun Kyaw

2. Stable Angina
• Classic angina is substernal chest discomfort
that occurs predictably and is relieved by rest
or nitroglycerin
• Stable pattern for >2 weeks

3. Classification ( CCS Grading )
Grade I Angina with strenuous exertion
(shoveling snow)
Grade II Mild limitation of normal activity
(walking up hill quickly)
Grade III Marked limitation of nl activity
(walking 1-2 blocks)
Grade IV Unable to do physical activity
(may occur even at rest)

4. 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
American Heart Association. Heart Disease and Stroke Statistics, 2009 Update.
Pepine CJ, et al. Am J Card. 1994;74:226-231.
New Cases of Stable Angina Per Year
(Among Americans ≥ 45 Years of Age)
Men Total
Incidence
(Number
of
New
Cases)
320,000
180,000
500,000
Women

5. Symptoms Other Than Classic Chest
Pain Are Common in Chronic Angina
Gender
Typical Angina
Symptoms
Atypical Angina
Symptoms
Male (n = 2249) 55%* 34%*
Female (n = 976) 28% 53%
– Shortness of breath
– Fatigue
– Weakness
– Lightheadedness
– Diaphoresis
– Nausea
– Indigestion
• Anginal equivalents are common
• In 3225 patients referred to Duke University for cardiac
catheterization, atypical angina symptoms were reported in
both men and women

6. Pain Symptoms Occur at the End
of the Ischemic Cascade
Magnitude
of
Ischemia
Stress Duration
↓ Relaxation
Systolic
Dysfunction
↓Diastolic
Filling
ECG 
PAIN
Biochemical
Alterations
ST alterations
Diastolic
Dysfunction
↓ Contraction

7. Myocardial Ischemia:
Unbalanced Oxygen Supply and Demand
Ischemia
Oxygen
Demand
Systolic
Pressure
Volume
Overload
Contractility
Heart Rate
LV Wall Tension
Oxygen
Supply
Coronary
Blood Flow
Coronary Perfusion
Pressure
Coronary
Vascular
Resistance
External
Compression
Intrinsic
Regulation

8. 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

9. Symptom
management
Aggressive
risk factor
reduction
Lifestyle
modification
Antiplatelet
therapy
Comprehensive management of myocardial ischemia

10. Symptoms of Angina Persist Despite
OMT ± PCI
88
34
28 26
87
42
33
28
0
20
40
60
80
100
Baseline 1 Year 3 Years 5 Years
PCI + OMT
OMT
Continuing
Angina
(%)
p < 0.001
p = 0.02
p = NS
p = NS
The COURAGE Study (N = 2287)
One-quarter to one-third of
patients had persistent
angina/ischemia despite
OMT ± PCI

12. Ischemia-CKD trial 2020

13. Beta Blockers
• Decreases oxygen demand by lowering heart
rate, myocardial contractility and wall stress
• Titrate resting HR to 50-60’s
• Typically use cardio-selective (metoprolol or
carvedilol , atenolol)
• Improves mortality in post MI and LV
dysfunction patients
• Dose related effect

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

15. 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)

16. 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

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

18. 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

19. 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

20. 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

21. Preconditioning: Nicorandil
Nitrate-associated effects
• Vasodilation of coronary epicardial arteries
Activation of ATP-sensitive K+ channels
• Ischemic preconditioning
• Dilation of coronary resistance arterioles
IONA Study Group. Lancet. 2002;359:1269-75.
Rahman N et al. AAPS J. 2004;6:e34.
N O
O NO2
HN

22. Nicorandil
• Dosage- 20mg bid
• Tolerance is seen with chronic dosage
• No cross tolerance with nitrates
• The Impact Of Nicorandil in Angina (IONA) trial
showed a significant reduction of major coronary
events in stable angina patients treated with
nicorandil compared with placebo as add-on to
conventional therapy
• Also used in unstable angina. It also reduces the
number of further attacks
• Additive effects with nitrates

23. Sinus node inhibition: Ivabradine
DiFrancesco D. Curr Med Res Opin. 2005;21:1115-22.
IVABRADINE
SA node
AV node Common bundle
Bundle branches
Purkinje fibers

24. Sinus node inhibition: Ivabradine
• If current is an inward
Na+/K+ current that
activates pacemaker
cells of the SA node
• Ivabradine
– Selectively blocks If in
a current-dependent
fashion
– Reduces slope of
depolarization,
slowing HR
DiFrancesco D. Curr Med Res Opin. 2005;21:1115-22.
40
20
0
–20
–40
–60
0.5
Potential (mV)
Control Ivabradine 0.3 µM
Time
(seconds)

25. Metabolic modulation (pFOX):
Trimetazidine
• O2 requirement of
glucose pathway is
lower than FFA
pathway
• During ischemia,
oxidized FFA levels
rise, blunting the
glucose pathway
FFA Glucose
Acyl-CoA
Acetyl-CoA
Pyruvate
Energy for contraction
Myocytes
β-oxidation
Trimetazidine
MacInnes A et al. Circ Res. 2003;93:e26-32.
Lopaschuk GD et al. Circ Res. 2003;93:e33-7.
Stanley WC. J Cardiovasc Pharmacol Ther. 2004;9(suppl 1):S31-45.
pFOX = partial fatty acid oxidation
FFA = free fatty acid

26. • It is piperazine derivative
• No significant negative inotropic or vasodilator
properties either at rest or during dynamic
exercise
• TRIMPOL II –RCT of 426 patients with CSA who
were randomised to either trimetazidine 20 mg
three times a day or placebo in addition to
metoprolol 50mg.
• This study demonstrated an improvement in time
to STsegment depression on exercise tolerance
testing (ETT), total exercise workload and angina
frequency in patients randomised to receive
trimetazidine

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

28. Ranolazine
(N-(2,6-dimethyphenyl)-4-[2-hydroxy-3- (2-
methoxyphenoxy)-propyl]-1-
piperazineacetamide)
is a substituted piperazine compound.
• pFOX inhibitor -that ranolazine only inhibits
fatty-acid oxidation during the periods of
elevated plasma FFA levels associated with
myocardial ischaemia
• Late sodium current blocker

29. Ischemic Myocyte
Peak 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.
‡

30. Ischemic Myocyte
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.
0
Sodium
Current
(mV)
Cardiac Sodium
Channel Current
Increased Late
Sodium Current
Peak Sodium Current (systole)
‡

31. 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.
Ischemic Myocyte
Late Sodium Current
Sodium-Calcium Exchanger
‡

32. Na+/Ca2+ overload and ischemia
Adapted from Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13.
 Late Na+ current
 Diastolic wall tension (stiffness)
Intramural small vessel compression
( O2 supply)
 O2 demand
Na+ overload
Ca2+ overload
Myocardial
ischemia

33. Understanding Angina at the Cellular
Level
 Ischemia impairs cardiomyocyte
sodium channel function
 Impaired sodium channel function
leads to:
 Pathologic increased late sodium
current
 Sodium overload
 Sodium-induced calcium overload
 Calcium overload causes diastolic
relaxation failure, which:
 Increases myocardial oxygen
consumption
 Reduces myocardial blood flow
and oxygen supply
 Worsens ischemia and angina
Ranolazine
Ischemia
↑ Late INa
Na+ Overload
Diastolic relaxation failure
Extravascular compression
Ca++ Overload

35. • Patients withdrawn from other anti-anginals
(N = 191 randomized)
• Randomized, double-blind, 4-period crossover
– 1-wk treatment periods
– Placebo vs 500, 1000, and 1500 mg bid
• Exercise tests after each week of treatment
– At trough (12 hr after dosing)
– At peak (4 hr after dosing)
Monotherapy Assessment of
Ranolazine In Stable Angina(MARISA )

36. Combination Assessment of
Ranolazine In Stable Angina CARISA
• Randomization criteria identical to MARISA except for background
therapy
– Atenolol 50 mg qd (n = 354), or
– Amlodipine 5 mg qd (n = 256), or
– Diltiazem CD 180 mg qd (n = 213)
• Three parallel groups for 12 wk of treatment
– Placebo
– Ranolazine 750 mg bid
– Ranolazine 1000 mg bid
• Exercise testing
– At trough after 2, 6, and 12 wk of treatment
– At peak after 2 and 12 wk of treatment

37. MARISA and CARISA Enrolled a Broad
Population of Chronic Angina Patients
Patients, %
N = 1014
Gender Male 77%
Female 23%
Age < 65 yr 49%
65 to < 75 yr 40%
≥ 75 yr 11%
Concomitant
disease
Diabetes 23%
Heart failure 27%
Hypertension 64%
Prior MI 57%
Prior PTCA, CABG orTMR 34%

38. 3 ranolazine trials

39. Baseline characterstics

43. NO MUCH BENEFIT IN ACS

44. The Anti-ischemic Effects of Ranexa Are
Independent of Hemodynamic Changes
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.
Minimal changes in mean heart rate (< 2 bpm)
and SBP (< 3 mm Hg) were observed in patients
treated with Ranexa in controlled clinical studies
8,000
12,000
16,000
20,000
24,000
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
RPP
(mm
Hg
×
bpm)
Exercise
Placebo (n = 244)
1000 mg bid Ranexa (n = 238)
CARISA

45. Ranolazine – hemodynamic affects
• No affect of Blood Pressure or Heart Rate
• Can be added to Conventional Medical
therapy, especially when BP and HR do not
allow further increase in dose of
BetaBlockers, Ca Channel blockers, and
Long Acting Nitrates.
• Ranolazine has twin pronged action.
1. pFOX
2. Late Na inward entry blockade

46. Contraindications
• 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

47. Cautions
• Ranolazine is known to increase the QT interval
• It blocks Ikr and hence prolongs the QT interval.
• Clinical experience - did not show an increased
risk of proarrhythmia or sudden death

48. Recommendations for Pharmacological
treatments in CCS ( ESC 2019 )

49. Recommendations for Pharmacological
treatments in CCS ( ESC 2019 )

50. Recommendations for Pharmacological
treatments in CCS ( ESC 2019 )

51. Physiologic Effects of
Antianginal Treatments
/
Beta-blockers
DHP CCBs
Non-DHP CCBs
Long-acting nitrates
Ranolazine
Revascularization
Therapy
Coronary
blood flow
Arterial
pressure
Venous
return
Myocardial
contractility
Heart
rate
O2 Demand
O2 Supply
/
1
2
2
2
2

52. Enhanced External Counterpulsation
• Increases BP and diastolic augmentation
• Improve coronary collateral flow
• Well tolerated
• 5 days per week x 7 weeks ( Total 35 times)
• 1 hour per day
• Approved only for patients with class III or IV
angina who are not candidates for revascularization
• Benefits are inconclusive

53. EECP

54. EECP - Enhanced External
CounterPulsation
Sequential
inflation of cuffs
• Retrograde aortic
pressure wave
• Increased Coronary
perfusion pressure
• Increased Venous
Return
• Increased Preload
• Increased Cardiac
Output
Simultaneous
deflation of
cuffs in late
Diastole
 Lowers Systemic
Vascular Resistance
 Reduced afterload
 Decreased Cardiac
workload
 Decreased Oxygen
Consumption

55. EECP - Enhanced External
CounterPulsation
• External, pneumatic compression of lower
extremities in diastole.

56. EECP improves angina class
73.4
39.5
22.0
0
10
20
30
40
50
60
70
80
≥1 class ≥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

57. EECP – Contraindications &
Precautions
• Arrhythmias that interfere with machine
triggering
• Bleeding diathesis
• Active thrombophlebitis & severe lower
extremity vaso-occlusive disease
• Presence of significant AAA
• Pregnancy

58. Transmyocardial Laser
Revascularization (TMLR)
• 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

60. Surgical laser TMR improves angina class
83
76
13
32
87
78
0
20
40
60
80
100
3 12
Time (months)
Improvement*
(% of patients)
TMR Medical Crossover from medical
Allen KB et al. N Engl J Med. 1999;341:1029-36.
N = 275 with CCS class IV angina
*Reduction of ≥2 CCS classes
†Due to treatment failure
TMR = transmyocardial revascularization
P < 0.001
TMR vs medical
(both time points)
†

61. Transmyocardial Laser
Revascularization – DIRECT trial

62. 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

64. Spinal Cord Stimulation
power source conducting wires electrodes at
stimulation site
Stimulation typically
administered for 1-2 hrs tid
Therapeutic mechanism appears to be alteration of anginal

66. Newer Drugs

67. • Allopurinol
– 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

68. • Testosterone (side effects)
• Stem cell therapy ( injections of autologous CD34+
cells)

69. Perhexilene
• Earlier designed as a CCB but does not act like a CCB
• It does not affect the heart rate or SVR
• Multiple randomised trials show that it has anti anginal
effect as monotherapy or as combination.
• Inhibition of CPT-1 and CPT-2, resulting in increased
glucose and lactate utilisation
• S/E hepatotoxicity and peripheral neuropathy due to
phospholipid accumulation as a result of CPT ½
inhibition.

70. Cardiac metabolism

71. Etomoxir/ Oxfenicine
• Potential anti anginal agent
• Launched as an anti-diabetic agent due to
hypoglycaemic effects
• CPT 1 Inhibitor
• Improvement in LV function in rats
• Single study available on humans (15 patients)
with NYHA II – III Etomoxir 80mg was
administered.
• Only animal studies on oxfenicine.

72. Rho kinase inhibition: Fasudil
• Rho kinase (ROCK) triggers vasoconstriction
through accumulation of phosphorylated
myosin
• Relaxes vascular smooth muscle

73. Rho kinase inhibition: Fasudil
Adapted from Seasholtz TM. Am J Physiol Cell Physiol. 2003;284:C596-8.
Ca2+ Ca2+
PLC
SR Ca2+
Receptor
Agonist
Myosin
Myosin-P
Myosin phosphatase
PIP2
IP3
MLCK
VOC ROC
Ca2+
Calmodulin
Rho
Rho kinase
Fasudil

74. Rho kinase inhibition: Fasudil
Fasudil up to 80 mg three times daily
significantly increased the ischemic threshold of angina
patients
during exercise with a trend toward increased exercise
duration.
Double-Blind, Placebo-Controlled, Phase 2 Trial on 84
patients
J Am Coll Cardiol. 2005;46(10):1803-1811

75. Rho kinase inhibition: Fasudil

76. Molsodomine & linsodomine
• Anti anginal and anti ischaemic
• Acts like nitrates
• Metabolises in liver to form linsodomine
• Orally active
• Metabolised in liver

77. 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

78. 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

79. Thank You !!