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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

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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