Dr. Dendi Puji Wahyudi, SpJP, FIHA. 3rd Pekanbaru Cardiology Update, August 24th 2013. Pangeran Hotel, Pekanbaru. Learn more at PerkiPekanbaru.com

1. Dendi Puji Wahyudi

2.  Angina pectoris is a syndrome characterized by
sudden severe pressing substernal chest pain or
heaviness radiating to the neck, jaw, back and
arms
 The primary cause is an imbalance between
myocardial oxygen demand and oxygen supplied
by coronary vessels, due to:
◦ a decrease in myocardial oxygen delivery
◦ an increase in myocardial oxygen demand
◦ or both

3.  Coronary artery blood flow is the primary determinant of
oxygen delivery to the myocardium
◦ Myocardial oxygen extraction from the blood is nearly complete,
even at rest
 Coronary blood flow is essentially negligible during
systole and is therefore determined by:
◦ Perfusion pressure during diastole (aortic diastolic pressure)
◦ Duration of diastole
◦ Coronary vascular resistance

4.  The major determinants of myocardial oxygen
consumption include:
◦ Ventricular wall stress
 Both preload (end-diastolic pressure) and afterload (end-
systolic pressure) affect ventricular wall stress
◦ Heart rate
◦ Inotropic state (contractility)
◦ Myocardial metabolism (glucose vs fatty acids)

5.  Stable angina: clinical syndrome characterized by
discomfort in the chest, jaw, shoulder, back or
arms
◦ Elicited by exertion or emotional stress
◦ Relieved by rest or nitroglycerin
 Term is usually confined to cases in which the
syndrome can be attributed to myocardial
ischemia

6.  Purpose of diagnosis & assessment :
◦ Confirmation of the presence of ischemia in patients with
suspected stable angina
◦ Identification or exclusion of associated conditions or
precipitating factors
◦ Risk stratification
◦ To plan treatment options
◦ Evaluation of the efficacy of treatment

7. Diagnosis and
Assessment
Pharmacological
management
Interventional
cardiology and
cardiac surgery
Patient issues and
follow up
Presentation
Chest pain
evaluation service
Drug intervention
to prevent new
vascular events
Stable angina and non-
cardiac surgery
Psychological and
cognitive issues
Journey of Angina Patient

8. Patient presents with chest pain
likely to be due to stable angina
Consider characteristics of pain
and associated features
Detailed clinical
examination
Consider need for
early referral
Refer for confirmation of
diagnosis to chest pain
service
Coronary
angiography
Exercise tolerance test or
Myocardial perfusion scintigraphy
if unable to exercise or pre
existing ECG abnormalities
12 Lead ECG
Measure Hb,
TSH, TC, RBS

9. Confirm diagnosis and assess severity of CHD
Use chest pain evaluation service with
earliest appointment
Early access to angiography and coronary artery bypass surgery
may reduce the risk of adverse cardiac events and impaired
quality of life

10.  Improve prognosis
 Decrease symptoms
◦ Medical treatments
 Hemodynamics
 If inhibitor
 Metabolic agents
◦ Revascularization
 PCI, CABG

11. Average angina
patients
4.9 drugsNitrates 72%
Beta blockers 69%
CCBs 44%
Anti-thrombotics 89%
ACEi 62%
Statins 47%

12. Angina attack per week 5.2
Nitroglycerin use per week 5.1
Angina at rest 27%
Angina during exercise 93%
Angina attack
nearly every
day!

13. TIBET, Dargie et al. IMAGE, Savonitto et al. CESAR, Knight et al.
Eur Heart J, 1996;17:96–103 JACC, 1996;27:311–316 Am J Cardiol, 1998;81:133–136
Atenolol, nifedipine SR & its combination Metoprolol, nifedipine SR & its combination Amlo + atenolol vs diltiazem + atenolol
No additive benefit from combination purported benefit of 2 drugs is due to addition of
new drug in resistant patients
Exercise test parameters don’t improve
when adding second hemodynamic drug
Akhras et al. Meyer et al. Madjlessi-Simon et al.
Lancet, 1991;338:1036–1039 Cardiovasc drugs ther, 1993;7:909–913 Eur Heart J, 1995;16:1780–1788
Atenolol, nifedipine SR, ISMN & its
combination
Atenolol, nifedipine SR & its combination Beta blockers, amlodipine & its combination
No substantial benefit to any combination
over beta blocker monotherapy
Combination therapy is no better
than atenolol alone
Combination provides no additional benefits
in patients resistant to beta blockers
All of these studies agree:
Combination of hemodynamic agents
is
NOT ENOUGH

14.  ONE patients out of THREE remains symptomatic
despite hemodynamic therapy
Boden et al. COURAGE STUDY. N Engl J Med 2007: 365: 1503-1516

15. Most patients with typical angina do not
have coronary atherosclerotic obstruction
Sambuceti G, Eur J Nucl Mol Imaging 2005; 32: 385-388. Chang VY et al., Circulation 2001; 124: 2423-2432
Many patients with coronary lesions do not
have ischemic heart disease

16. Everyday …
Beats 100,000 times
Pumps 7,000 liters of blood through the body
Needs 6 kg of ATP to function
◦ 20-30 times its own weight

17.  Maximize the use of O2 to make more ATP available
“ Metabolically acting agents protect from ischaemia by
increasing glucose metabolism relative to that of fatty
acids” 1
“may be used in
combination therapy with haemodynamically acting
agents, as their primary effect is not through reduction in
heart rate or blood pressure” 1
1. Guidelines on the management of stable angina pectoris – ESC 2006

18. O2 + Glucose
Lactate Pyruvate
O2 + Fatty Acids
ATP
Glucose Oxidation
•Provides 10-40% Energy
•More O2 efficient
•1 O2 yields 6.4 ATP
Fatty Acids Oxidation
•Provides 60-90% Energy
•Less O2 efficient
•1 O2 yields 5.6 ATP

20. Glucose
Lactate Pyruvat
e
Fatty Acids
ReducedReduced
ATPATP
productioproductio
nn
• Pyruvate to Lactate
• Cell Acidosis
• Calcium Overload
Increased Fatty Acid
Oxidation Rate
Need more
ATP

21. Glucose
Lactate Pyruvat
e
Fatty Acids
ReducedReduced
ATPATP
productioproductio
nn
• Pyruvate to Lactate
• Cell Acidosis
• Calcium Overload
Increased Fatty Acid
Oxidation Rate
Need more
ATP
Trimetazidine MR
partially inhibits
Fatty Acid
pathway
IncreasedIncreased
ATPATP
productioproductio
nn
More Effective

22.  Lowers fatty acid oxidation, increase glucose &
lactate oxidation
 Selective KAT-3 inhibitor
Optimize use of oxygen, reduce acidity in
tissue, improve cardiac function & contractility
during ischemia while maintaining cell
membrane homeostasis
Does not interfere heart
rate & blood pressure

23.  Partial inhibition of enzyme KAT-3 (last step of beta
oxidation from Fatty Acid pathway)
 Trimetazidine MR increases myocardial energy during
ischemia
 More effective ATP synthesis

24. Management of stable angina pectoris. Recommendations from the Task Force of the ESC. Eur Heart J. 2006; 27:1341-81.
“The ischaemic cascade is characterized by a sequence of
events, resulting in metabolic abnormalities, perfusion
mismatch, regional and then global diastolic and systolic
dysfunction, electrocardiographic (ECG) changes, and angina.”
Angina
ECG Change
Cardiac Dysfunction
Metabolic
Change
Perfusion
Prevents ischemic cascade
Right from the start

25. Nesukay E. Circulation 2012
Trimetazidine MR
Less angina, less nitroglycerin consumption…
no matter how you combine it

26. Less angina, less nitroglycerin consumption
Glezer MG. PARALLEL study. Eur Heart J. 2007;28(Abst Suppl):770.
Mean weekly
nitroglycerin consumption
0
10
20
30
40
50
60
70
80
Mean weekly
number of angina attacks
P<0.0001 P<0.0001
Meanevolutionbetween
baselineandweek-12(%)
-76% -79%
Trimetazidine MR
ISDN
n=903

27. Preserves cardiac function as early as 3rd
month
33.230.6
42.4
33.3
0
10
20
30
40
50
Baseline 3-months
LVEF(%)
*
* P<0.05 vs baseline
† P<0.01 vs baseline
‡ P<0.05 vs placebo
n=87
†‡
+9,5%
Control Trimetazidine
MR
Gunes Y, et al. Heart Vessels. 2009;24:277-282.

28. 0
5
10
15
Without Trimetazidine MR
IncidenceofMACE(%)
Primary end point: MACE
JS KIM. Korean Circulation 2010 Autumn Poster 21
65%65%

29. Total mortality Hospitalization
Control Trimetazidine MR
Cumulativesurvival(%)
Patientsfreeof
Hospitalizationl(%)
Reduction of -56%
of the total mortality rate
Reduction of -47%
of the hospitalization rate
n=63
Di Napoli P, et al. J Cardiovasc Pharmacol. 2007;50:585-589.

30. -70
-60
-50
-40
-30
-20
-10
0
Nitrates CCB Nicorandil Trimetazidine
MR
6 month all cause mortality risk with different anti
angina treatments
Iyengar & Rosano, Am J Cardiovasc Drugs. 2009 ; 9 (5): 293-297
-64%

32. Rosano G, et al. Int J Cardiol. 2007:79-84
Protects diabetic patients against
silent myocardial ischemia

33.  Many patients continue to experience angina despite
medical therapy and/or revascularization
 Metabolic agent are a potentially effective new
antianginal option with a mechanism of action
complementary to traditional agents
 Potential clinical application in broad range of patients
unresponsive to current treatment options
◦ Elderly
◦ Diabetes
◦ LV dysfunction or heart failure