Different Faces of Angina Patients:

Challenges in Angina Management

Prof R Mohammad Yogiarto

Dr Soetomo Academic General Hospital

Faculty of Mediciine
AIRLANGGA UNIVERSITY
 Multiple "faces" of angina
% of patients
Chest tightness/ 67.7%
Heaviness 66.4%
55.6%
Chest pain
61% *
Breathing 47.9%
difficulties 55.4% *
Arrhythmia/ 20.5%
Tachycardia 28.7% *
Fatigue
53.7%
58.3%
Arm pain
21.7%
24.9%
Strong sweat
17.2%
13.9%
Nausea/Vomiting
7.6%
7.8% Man (n=1411)
16.6% Women (n=554)
Dizziness
24.9% *
Stress/Anxiety/ 29.6%
Depression 34.3% *
Jaw/Neck pain
12%
14.1%

Ambrosio G et al. Angiology 2019:70(5):397-406

 Angina Pectoris: Where are we now?

ECONOMICAL & PERSONAL BURDEN

Higher risk of

x3 x1.5 x4
DISABILITY1 JOB LOSS2 DEPRESSION1

1. Jespersen L et al. Clin Res Cardiol. 2013;102:571-581.

2. Padala SK et al. J Cardiavascular Pharmacol Ther. 2017;22(6):499-510.
 Angina Pectoris : Where are we now?

1. Vos T et al. Lancet. 2012;380:2163-2196.

2. Benjamin EJ et al. Circulation. 2017;135:e146-e603.
3. Eisen A et al. J Am Heart Assoc. 2016;5:e004080.
 Persistent ischemia (angina) despite
current drug therapy

◼ Despite use of traditional antianginal agents

(-blockers, CCBs, and nitrates), patients reported a
median
of 2 anginal attacks/week

◼ A significant percentage of patients have relative

intolerance to full doses of -blockers, CCBs, and nitrates

◼ -blockers and many CCBs have similar depressive

effects on BP, HR and/or AV nodal conduction

◼ Antianginal drugs without these limitations are needed

Gibbons RJ et al. ACC/AHA 2002 guidelines.
Gibbons RJ et al. ACC/AHA 2002 guidelines.
www.acc.org/clinical/guidelines/stable/stable.pdf
www.acc.org/clinical/guidelines/stable/stable.pdf
Pepine CJ et al. Am J Cardiol. 1994;74:226-31.
Pepine CJ et al. Am J Cardiol. 1994;74:226-31.
Persistent ischemia (angina) despite optimal
revascularization
Arterial Revascularization Therapies Study

~60% to 80%
taking antianginal
medication
~10 to 20%
had angina

*1 year after optimal revascularization

(stenting or surgery) for ischemia relief
(not to prolong survival) Serruys PW et al. N Engl J Med. 2001;344:1117-24.
 Patients without obstructive CAD experience an angina
burden at least as high as those with obstructive CAD

60
P=0.038 P=0.002 P=0.012 P=0.199
50
Prevalence of angina (%)

40

30

20

10

0
Obstructive Not Obstructive Not Obstructive Not Obstructive Not
obstructive obstructive obstructive obstructive
n=5539
Baseline 1 month 6 months 12 months

CAD: coronary artery disease

Grodzinsky A, Arnold SV, Gosch K, et al. Angina frequency after acute myocardial infarction in patients without obstructive coronary artery disease. Eur Heart J
Qual Care Clin Outcomes. 2015;1(2):92-99.
Clogged Pipe Theory in
Ischemic Heart Disease

Libby P, N Engl J Med 2013;368:2004-13

 According to this model:

1. Ischemic Heart Disease is caused by atherosclerotic obstructions of the

coronary vessels

2. The demonstration of such atherosclerotic obstructions is the key to

diagnosis

3. Removal of such coronary obstructions with CABG and PCI is the key to
treatment
 What actually causes angina?
Angina is due to Myocardial ischemia = mismatch between substrate delivery and
cardiomyocyte requirements

◼ Although, there is a direct relationship between obstructive CAD and myocardial ischemia, there are many
other contributor
Thus, myocardial ischemia ≠ obstructive CAD, or
◼ obstruction does not necessarily imply presence of ischemia, and
◼ absence of obstruction does not necessarily imply absence of ischemia
 Structural and Funtional disorder of the Coronary Circulation

Ford TJ, et al. Heart 2018;104:284–292. doi:10.1136/heartjnl-2017-311446

 Multifactorial origin of angina
Coronary microcirculation

Arteriole
Capillaries

Functional mechanisms
Microvascular spasm
Structural mechanisms
◼ Adverse arteriolar remodeling ◼ Intravascular plugging
→ Increased medical
◼ Perivascular fibrosis Abnormal vasodilation
wall thickness
→ Intimal thickening ◼ Capillary rarefaction
→ Reduced wall/lumen ration
Microvessel
Occlusive CAD unable to dilate
Myocardial factors affecting microvascular function
Endothelial dysfunction
◼ Left ventricular hypertrophy ◼ Increased intramyocardial and/or VSMC dysfunction
◼ Reduced diastolic time pressure
Coronary spasm ◼ Increased intracavitary
◼ Calcium overload
pressure
◼ Amyloidosis ◼ Tissue edema

Kaski JC et al. Circulation. 2018;138(14):1463-1480.

 Atherosclerosis is only part of story,
other mechanism is working as well

These STRUCTURAL and FUNCTIONAL phenomena can act

simultaneously in the same patient
Crea F et al. Eur Heart J 2014;35(17):1101-11 Thygesen K et al. Eur Heart J. 2018;00:1-33
 Under-recognition of angina is associated with less
chance of treatment optimization

Qintar et al. Eur Heart J – Quali Care Clin Outcomes. 2016: 2(3); 208-214
 Angina is a single clinical entity with multiple
etiologies that requires a comprehensive approach

Coronary Myocardial cells1,2

vessels

Large coronary vessels1

• Flow-limiting stenosis
• Endothelial dysfunction
• Vasospasm
• Impaired energy metabolism1
• Muscle bridge
• Defective cellular oxygen transport1
• Inflammation
Small coronary vessels1 • Mitochondrial dysfunction/adaptation1
• Microvascular dysfunction • Inflammation/fibrosis2,3
• Endothelial dysfunction • ROS production, which can induce cellular
• Spasm damage3
• Inflammation • Promotion of programmed cell death2,3
• Microemboli ROS: reactive oxygen species

1. Pepine CJ, Douglas PS. Rethinking stable ischemic heart disease: is this the beginning of a new era? J Am Coll Cardiol. 2012;60(11): 957-959. 2. Brown DA, Perry JB,
Allen ME, et al. Expert consensus document: mitochondrial function as a therapeutic target in heart failure. Nat Rev Cardiol. 2017;14:238-250. 3. Fillmore N, Mori J, 1
Lopaschuk GD. Mitochondrial fatty acid oxidation alterations in heart failure, ischaemic heart disease and diabetic cardiomyopathy. Br J Pharmacol. 2014;171:2080-2090.
Knuuti J et al. Eur Heart J 2020;41(3):407-77
 Medical treatment in patients with CCS –
a stepwise approach....adapted to the patient

Knuuti J et al. Eur Heart J 2020;41(3):407-77

Comparison between antianginal drugs

Ferrari R et al. Eur Heart J 2019;40(2):190-4

 60% to 70 % of patients with persistent/recurrent angina after primary PCI
don’t receive additional anti-angina therapy on top of the b-blocker

Fanaroff et al., JOURNAL of American Heart Association 2017

 Chronic Coronary Syndrome is a multifactorial disease which
needed comprehensive treatment

Hemodynamic
Approach
Metabolic Approach
• Betablockers
• CCB Trimetazidine
• Long Acting nitrates Directly at Cardiac Cell Level
• Ivabradine
• PCI……

Adapted from Pepine CJ. J Am Coll Cardiol. 2012;60:957‐959 and Brown DA. et al. Nat Rev Cardiol. 2017
Apr;14:238‐250.
 Temporal sequence of pathophysiologic events
The
initiated an ischemic cascade imbalance
oxygen supply/demand

Myocardial oxygen supply/demand imbalance

Early
intervention
Time from onset of ischemia

Inadequate Hypoxia and Myocardial Ischaemic Angina

myocardial metabolic contractile ECG changes
perfusion abnormalities impairment
 MYOCARDIAL ENERGY METABOLISM (Normal state)

LACTATE Glucose FATTY ACID

H+ Na+ Na + Ca 2+

(2 ATP) H+ Na+ Na+ Ca

2+
Acyl
LACTATE
Pyruvate CoA
With the same amount of ATP produced, the fatty
acid oxidation consumes 15% more oxygen than
glucose oxidation. CPT1
LDH


PDH

PDH = Pyruvate Acetyl Beta

Acetyl
oxidation
dihydrogenase
CoA CoA 3-KAT
LDH = Lactate
dihydrogenase

KREB’S CYCLE ATP 3-KAT = 3-ketoacyl CoA thiolase

 MYOCARDIAL METABOLISM
DURING ISCHAEMIA / HYPOXIA

◼ Excess FFA metabolism

◼ FFA oxydation require 10-15% more oxygen than
glucose oxydation
◼ Increase FFA oxydation leads suppresive glucosa
oxydation as a result PDH inhibition
◼ Accumulation of lactate and protons in ischaemic cell
◼ Acidosis, reduction in contractile function
◼ Diastolic /systolic dysfunction during ischaemia
 In Ischemic State
LACTATE Glucose FATTY ACID
H+ Na+ +
Na Ca 2+

(2 ATP) H+ Na+ Na+ Ca 2+

Acyl
LACTATE
Pyruvate CoA
CPT1

LDH

PDH

Acetyl Beta
Acetyl
oxidation
CoA CoA 3-KAT

KREB’S CYCLE ATP

Mitochondria in the ischemic state

TMZ

Guarini G et al. Trimetazidine and other metabolic modifiers. Eur Cardiol. 2018;13(2):104-111
 Metabolic modulation (pFOX): Trimetazidine

Myocytes
◼ O2 requirement of glucose
FFA Glucose
pathway is lower than FFA
pathway
Acyl-CoA Pyruvate
◼ During ischemia, oxidized FFA
levels β-oxidation
rise, blunting the glucose
Trimetazidine
pathway
Acetyl-CoA

Energy for contraction

MacInnes A et al. Circ Res. 2003;93:e26-32.
pFOX = partial fatty acid oxidation Lopaschuk GD et al. Circ Res. 2003;93:e33-7.
FFA = free fatty acid Stanley WC. J Cardiovasc Pharmacol Ther. 2004;9(suppl 1):S31-45.
 InofIschemic
The Role Trimetazidine :State
3-KAT inhibitor
LACTATE GLUCOSA FATTY ACID
H+ Na+ Na + Ca 2+

(2 ATP) H+
N Na+ Na+ Ca2+ N Acyl
LACTATE Pyruvate
CoA
CPT1

LDH

PDH 

Acetyl Beta
Acetyl
oxidation
TRIMETAZIDINE
CoA CoA 3-KAT

KREB’S CYCLE ATP

 Trimetazidine has a unique mode of action

DIRECTLY AT THE CARDIAC …FOR THE PATIENTS’

CELL LEVEL BENEFIT

Strikes at the beginning Rapid and significant

of the ischemic cascade1 antianginal efficacy4

Reduces
Reduces cellular acidosis2
angina symptoms4

Increases exercise
Increases ATP by 33%3
capacity4
Treating angina w here it
m atters
1. Fillmore N et al. B r J P ha rma col. 2014;171(8):2080-2090. 2. Kantor PF et al. C irc R es. 2000;86(5):580-588.
3. Fragasso G et al. E ur H ea rt J. 2006;27(8):942-948. 4. Glezer M, CHOICE-2 study investigators. A dv T her. 2018;35(7):1103-1113
3
 Trimetazidine is comparable with Beta Blocker in Total
Exercise Duration Improvement

Detry et al. Br J Clin Pharmac. 1994;37:279-288.

 Trimetazidine can be associated with any antianginal drugs

TMZ TMZ TMZ TMZ

Large scale, multicenter, 6 months, open-label observational study on 896 patients with stable angina pectoris

Glezer M and CHOICE-2 study investigators. Real-world evidence for the antianginal efficacy of trimetazidine from the Russian Observational CHOICE-2 Study. Adv Ther. 2017;34(4):915-924
Trimetazidine in newly diagnosed patients with CCS

Glezer M; CHOICE-2 study investigators. The effectiveness of trimetazidine treatment in patients with stable angina pectoris of various durations: Results from the CHOICE-2 Study. Adv Ther. 2018;35(7):1103-13
 Hemodynamic and metabolic combination approach
provide optimal benefit

HR х SBP

Ischemic threshold
Metabolic
approach
Delay the reach
of Ischemic
threshold with a
Hemodynamic hemodynamic
approach approach

1
Exercise capacity

Marzilli M. Eur Heart J Supplements 2001; 3 (Suppl O): O12–O15)

 Trimetazidine is acting at cardiac cell and provides
comprehensive approach

1. Kantor PF, et al. Circ Res. 2000;86:580‐588. 2. Fragasso G, et al. American Heart Journal. 2003;146. 3. Maridonneau‐Parini I. Clin Pharmacol.
1985;20:148‐51. 4. Belardinelli R, et al Eur H Journal. 2007;28:1102‐1108. 5. Yoon JW et al. Int J Card. 2013;167:126‐133. 6. Di Napoli P, et al.
Nitric Oxide. 2007;16:228‐36. 7. Danikiewicz A, et al. Can J Physiol Pharmacol. 2017;95:759‐762. 8. Belcher PR. Cardiovasc Drugs Ther.
1993;7:149‐57.
 Trimetazidine in different Guidelines

Therapeutic Strategy for Symptom Control

Aggressive risk factor control Short-acting Nitrates

1ª line -Blockers

Trimetazidine should be used in Ca2+ Channel Blockers

symptomatic patients with 2ª line
stable angina on beta-blockers
Trimetazidine Ivabradine
(or other antianginalTrimetazidine
drugs), or should be used in
in patients with stable anginawith stable angina
patients
and left ventricular dysfunction.
undergoing myocardial
LOR: IIa revascularization procedures
(either PCI or CABG) to
decrease the extent of 3ª line Long-acting Nitrates
myocardial injury LOR: IIa

César LAM et al. Guideline for stable coronary artery disease. Arq Bras Cardiol. 2014;103(2 Suppl 2):1-56
Trimetazidine antianginal efficacy has been reinforced
New recommendations by the ESC

In selected patients, the combination

of a beta-blocker or a CCB with
trimetazidine may be considered for
first-line treatment according to
heart rate, BP, and tolerance.
Knuuti J et al. Eur Heart J 2020;41(3):407-77
 New Consensus on INOCA confirmed multifactorial
origin of ischemia

◼ INOCA prevalence: A large proportion of patients (up to 70 %) undergoing coronary

angiography because of angina and evidence of myocardial ischemia do not have
obstructive coronary arteries but have demonstrable ischemia.
◼ INOCA is a confirmation of the multifactorial origin of chronic ischemia, where
microvascular dysfunction (MVD) and coronary spasm as the main endotypes of INOCA
are important pathogenic mechanisms
 Trimetazidine antianginal efficacy has been reinforced
New recommendations in INOCA Consensus

Trimetazidine
Kunadian V et al. Eur Heart J 2020;(0):1-217
 Trimetazidine OD An innovative &
unique technology
Multi-layer microgranules for
a powerful antianginal efficacy & relief

Hard capsule

Core granule
Drug layer
Coating layer

SmPC Trizedon 80 OD
 Take-home message

• Chronic Coronary Syndrome (CCS) is a multifactorial syndrome; diagnosis and

treatment of CCS must address multiple mechanism
• New INOCA consensus confirmed multifactorial origin of ischemia
• Treating angina patient must be adapted to each patients’ characteristic and preferences
including take into consideration their co-morbidities
• Medical treatment of CCS should be started immediately and maintain as long as
possible
• Trimetazidine strikes at the beginning of ischemic cascade, and with association with
BB, will further reduce angina symptoms, and increases exercise capacity and QoL in
patients
• New once-daily Trimetazidine OD formulation provides symptom control
THANK YOU