Dendi Puji Wahyudi
 Angina pectoris is a syndrome characterized by
sudden severe pressing substernal chest pain or
heaviness radiating to th...
 Coronary artery blood flow is the primary determinant of
oxygen delivery to the myocardium
◦ Myocardial oxygen extractio...
 The major determinants of myocardial oxygen
consumption include:
◦ Ventricular wall stress
 Both preload (end-diastolic...
 Stable angina: clinical syndrome characterized by
discomfort in the chest, jaw, shoulder, back or
arms
◦ Elicited by exe...
 Purpose of diagnosis & assessment :
◦ Confirmation of the presence of ischemia in patients with
suspected stable angina
...
Diagnosis and
Assessment
Pharmacological
management
Interventional
cardiology and
cardiac surgery
Patient issues and
follo...
Patient presents with chest pain
likely to be due to stable angina
Consider characteristics of pain
and associated feature...
Confirm diagnosis and assess severity of CHD
Use chest pain evaluation service with
earliest appointment
Early access to a...
 Improve prognosis
 Decrease symptoms
◦ Medical treatments
 Hemodynamics
 If inhibitor
 Metabolic agents
◦ Revascular...
Average angina
patients
4.9 drugsNitrates 72%
Beta blockers 69%
CCBs 44%
Anti-thrombotics 89%
ACEi 62%
Statins 47%
Angina attack per week 5.2
Nitroglycerin use per week 5.1
Angina at rest 27%
Angina during exercise 93%
Angina attack
near...
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 C...
 ONE patients out of THREE remains symptomatic
despite hemodynamic therapy
Boden et al. COURAGE STUDY. N Engl J Med 2007:...
Most patients with typical angina do not
have coronary atherosclerotic obstruction
Sambuceti G, Eur J Nucl Mol Imaging 200...
Everyday …
Beats 100,000 times
Pumps 7,000 liters of blood through the body
Needs 6 kg of ATP to function
◦ 20-30 time...
 Maximize the use of O2 to make more ATP available
“ Metabolically acting agents protect from ischaemia by
increasing glu...
O2 + Glucose
Lactate Pyruvate
O2 + Fatty Acids
ATP
Glucose Oxidation
•Provides 10-40% Energy
•More O2 efficient
•1 O2 yiel...
Glucose
Lactate Pyruvat
e
Fatty Acids
ReducedReduced
ATPATP
productioproductio
nn
• Pyruvate to Lactate
• Cell Acidosis
• ...
Glucose
Lactate Pyruvat
e
Fatty Acids
ReducedReduced
ATPATP
productioproductio
nn
• Pyruvate to Lactate
• Cell Acidosis
• ...
 Lowers fatty acid oxidation, increase glucose &
lactate oxidation
 Selective KAT-3 inhibitor
Optimize use of oxygen, re...
 Partial inhibition of enzyme KAT-3 (last step of beta
oxidation from Fatty Acid pathway)
 Trimetazidine MR increases my...
Management of stable angina pectoris. Recommendations from the Task Force of the ESC. Eur Heart J. 2006; 27:1341-81.
“The ...
Nesukay E. Circulation 2012
Trimetazidine MR
Less angina, less nitroglycerin consumption…
no matter how you combine it
Less angina, less nitroglycerin consumption
Glezer MG. PARALLEL study. Eur Heart J. 2007;28(Abst Suppl):770.
Mean weekly
n...
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 ...
0
5
10
15
Without Trimetazidine MR
IncidenceofMACE(%)
Primary end point: MACE
JS KIM. Korean Circulation 2010 Autumn Poste...
Total mortality Hospitalization
Control Trimetazidine MR
Cumulativesurvival(%)
Patientsfreeof
Hospitalizationl(%)
Reductio...
-70
-60
-50
-40
-30
-20
-10
0
Nitrates CCB Nicorandil Trimetazidine
MR
6 month all cause mortality risk with different ant...
Rosano G, et al. Int J Cardiol. 2007:79-84
Protects diabetic patients against
silent myocardial ischemia
 Many patients continue to experience angina despite
medical therapy and/or revascularization
 Metabolic agent are a pot...
Angina Management with Metabolic Agents
Angina Management with Metabolic Agents
Angina Management with Metabolic Agents
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Angina Management with Metabolic Agents

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

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  • 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 &amp; 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 &amp; 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 &amp; maximize oxygen use, especially during ischemia In normal cells, ATP mainly synthesized from glucose &amp; 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
  • Angina Management with Metabolic Agents

    1. 1. Dendi Puji Wahyudi
    2. 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. 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. 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. 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. 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. 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. 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. 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. 10.  Improve prognosis  Decrease symptoms ◦ Medical treatments  Hemodynamics  If inhibitor  Metabolic agents ◦ Revascularization  PCI, CABG
    11. 11. Average angina patients 4.9 drugsNitrates 72% Beta blockers 69% CCBs 44% Anti-thrombotics 89% ACEi 62% Statins 47%
    12. 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. 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. 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. 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. 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. 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. 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
    19. 19. 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
    20. 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 Trimetazidine MR partially inhibits Fatty Acid pathway IncreasedIncreased ATPATP productioproductio nn More Effective
    21. 21.  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
    22. 22.  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
    23. 23. 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
    24. 24. Nesukay E. Circulation 2012 Trimetazidine MR Less angina, less nitroglycerin consumption… no matter how you combine it
    25. 25. 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
    26. 26. 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.
    27. 27. 0 5 10 15 Without Trimetazidine MR IncidenceofMACE(%) Primary end point: MACE JS KIM. Korean Circulation 2010 Autumn Poster 21 65%65%
    28. 28. 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.
    29. 29. -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%
    30. 30. Rosano G, et al. Int J Cardiol. 2007:79-84 Protects diabetic patients against silent myocardial ischemia
    31. 31.  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
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