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
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
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
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.
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.
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
Notas del editor
Our aim when treating angina are usually to improve prognosis (using drugs such as lipid lowering agents, aspirin, etc) and to decrease symptoms To decrease symptoms we can give medical treatments, or when needed, revascularization procedures
It might not surprise you that angina patients in average take 5 drugs (ATP survey) As you can see here, most of them will be given Nitrates & beta blockers to alleviate symptoms
With the cocktail of drugs, how is our patients doing? In average, patients feels angina attack 5 times a week- that’s nearly every day with pain! It is clear that beta blockers alone are not enough!
Where hemodynamic agents merely by controlling supply & demand of blood to organs, metabolic agents are different. Metabolic agent, such as TRIZEDON MR, maximize the use of oxygen to make more ATP available. TRIZEDON MR is also recommended in ESC guideline (P.36 ESC guideline 2006 angina)
TRIZEDON works in cell metabolic level, not the same with hemodynamic agents. It maximizes the ATP synthesis & maximize oxygen use, especially during ischemia In normal cells, ATP mainly synthesized from glucose & fatty acid. Fatty acid consumes more oxygen, but also produces more ATP TRIZEDON MR works by partially inhibiting one of the enzyme in fatty acid beta oxidation process The key here is partially , if blocked entirely, Acyl CoA from FA oxidation will not be produced and cell membrane damage will result – which accumulates in form of arrhytmia If not blocked, then the drug wont have any effect
During ischemia, this is what happened : There’s an increase in fatty acid oxidation, which will… Inhibit glucose oxidation, causing… Anaerobic glycolysis, where glucose is turned in to lactate. When this happen, Cell experiences acidosis and therefore, more ATP is needed During more severe ischemic episode, only ATP from anaerobic glycolysis will be produced
During ischemia, this is what happened : There’s an increase in fatty acid oxidation, which will… Inhibit glucose oxidation, causing… Anaerobic glycolysis, where glucose is turned in to lactate. When this happen, Cell experiences acidosis and therefore, more ATP is needed During more severe ischemic episode, only ATP from anaerobic glycolysis will be produced
How TRIZEDON works Therefore, TRIZEDON is very useful during ischemia. How is it useful? (next slide)
As ESC mentioned in its guideline, ischemic cascade is caused by sequence of events which eventually causes angina With TRIZEDON, we alter the metabolic process in the heart muscle, hence reducing angina
In KAMIR registry: done in Korea- involving nearly 15,000 patients with AMI 65% reduction of MACE in 12 months KAMIR result was presented in WCC 2012 recently
Trimetazidine and reduction in mortality and hospitalization in patients with ischemic dilated cardiomyopathy