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Anginal pectoris refractory to standard medical therapy i

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Anginal pectoris refractory to standard medical therapy i

  1. 1. Refractory angina: The scope for ranolazine. Dr. B. K. Iyer
  2. 2. Chronic / Refractory angina <ul><li>What is this condition? </li></ul><ul><li>It is the disabling chest pain that persists </li></ul><ul><ul><li>Despite lifestyle adjustment and </li></ul></ul><ul><ul><li>Despite optimal medical therapy and </li></ul></ul><ul><ul><li>Despite invasive coronary interventions. </li></ul></ul>
  3. 3. Correlation - symptom severity and ischaemic burden <ul><li>1. Pain out of proportion to ischaemia </li></ul><ul><ul><li>20% of patients undergoing angiography because of angina have normal coronary arteries </li></ul></ul><ul><li>2. Ischaemia with no pain </li></ul><ul><ul><li>70% ischaemic episodes in the community are silent </li></ul></ul><ul><ul><li>25% of infarcts are silent </li></ul></ul><ul><li>3. No significant differences in objective measures of ischaemia between patients with angina and silent ischaemics </li></ul><ul><ul><li>Klein et al. Circulation 1994;89:1958-66 </li></ul></ul><ul><ul><li>See also Warren J. NEJMS 1812;1:1-11 </li></ul></ul>
  4. 4. Correlation - anxiety and ischaemic burden ‘ Angina is damaging my heart ’ Restricted lifestyle Increasing anxiety, depression Reduced activity Deconditioning Worsening symptoms at lower thresholds
  5. 5. Correlation – doctor’s demands and patient expectations I have this new operative approach that will help you Why don’t we ask him what he wants? How about EECP & angiogenesis? Thanks Doc; but once is enough. Any new medicines? The patient-centered approach
  6. 6. Angina Pectoris - Understanding the options when Standard Therapy Fails Dr. B. K. Iyer
  7. 7. Basis <ul><li>Patients experience angina despite medical therapy & / or revascularization </li></ul><ul><li>Clinical variations in broad range of patients unresponsive to current treatment options </li></ul><ul><ul><li>Elderly </li></ul></ul><ul><ul><li>Diabetes </li></ul></ul><ul><ul><li>LV dysfunction or heart failure </li></ul></ul><ul><li>Late Na + blockade is a potentially effective new antianginal option with a mechanism of action complementary to traditional agents </li></ul>
  8. 8. CAD: Multiple treatment options Reduce symptoms Treat underlying disease Lifestyle intervention Alternative TX Medical therapy PCI & CABG
  9. 9. CAD: Multiple treatment options Reduce symptoms Treat underlying disease PCI & CABG Lifestyle intervention Alternative TX Medical therapy
  10. 10. Invasive Treatment of CAD <ul><li>Acute Coronary Syndrome and Acute MI </li></ul><ul><ul><li>Aggressive treatment unquestionably shown to save lives and reduce future MIs. </li></ul></ul><ul><li>Stable Angina Pectoris </li></ul><ul><ul><li>What is the role of Coronary Revascularization ? </li></ul></ul><ul><li>CABG is better than Medical Therapy for </li></ul><ul><ul><li>3 vessel disease </li></ul></ul><ul><ul><li>CAD that involves Prox LAD (European Coronary Surgery Study) </li></ul></ul><ul><ul><li>3 vessel CAD with low EF (CASS) </li></ul></ul>
  11. 11. PCI in chronic angina and stable CAD <ul><li>PCI improves angina and exercise capacity </li></ul><ul><li>However, compared to optimal medical therapy, does PCI </li></ul><ul><ul><li>Prolong survival? </li></ul></ul><ul><ul><li>Reduce risk of subsequent MI? </li></ul></ul><ul><ul><li>Reduce hospitalization for unstable angina? </li></ul></ul><ul><ul><li>Decrease need for subsequent CABG? </li></ul></ul><ul><ul><li>Improve quality of life? </li></ul></ul>
  12. 12. 55 yr old female with stable angina
  13. 13. Revascularization for Stable CAD <ul><li>Acute Coronary Syndrome and Acute MI </li></ul><ul><ul><li>Clearly shown to improve survival </li></ul></ul><ul><li>Chronic Stable Angina </li></ul><ul><ul><li>Goal may be to just reduce symptoms and improve quality of life </li></ul></ul><ul><li>1 year after PCI or CABG </li></ul><ul><ul><li>25 to 60% of patients still have ongoing angina </li></ul></ul><ul><li>Many patients are deemed “inoperable” </li></ul><ul><ul><li>Condition not suitable for PCI or CABG </li></ul></ul><ul><ul><li>Co-morbidities make procedure too high risk </li></ul></ul>Benefit Risk
  14. 14. CAD: Multiple treatment options Reduce symptoms Treat underlying disease PCI & CABG Lifestyle intervention Alternative TX Medical therapy
  15. 15. SAFE-LIFE: Evaluation of intensive lifestyle intervention Michalsen A et al. Am Heart J. 2006;151:870-7. Advice on Mediterranean diet Stress management ≥30 min daily Encouraged to  physical activity 3-day nonresidential retreat Weekly 3-hr meetings x 10 weeks Biweekly 2-hr meetings x 9 months Control group received printed lifestyle advice only N = 101 with CAD
  16. 16. SAFE-LIFE: Reduction in angina at 1 year with intensive lifestyle intervention Michalsen A et al. Am Heart J. 2006;151:870-7. P = 0.015 P = 0.01
  17. 17. CAD: Multiple treatment options Reduce symptoms Treat underlying disease PCI & CABG Lifestyle intervention Alternative TX Medical therapy
  18. 18. Chronic CAD – Conventional Medical therapy <ul><li>Decrease Myocardial Oxygen demand </li></ul><ul><ul><li>Decrease in HR (Beta blockers and some Calcium Channel Blockers) </li></ul></ul><ul><ul><li>Decrease in Myocardial Contractility (BB and some CCBs) </li></ul></ul><ul><li>Increase Oxygen supply </li></ul><ul><ul><li>Long Acting Nitrates </li></ul></ul><ul><ul><li>Calcium Channel Blockers </li></ul></ul>
  19. 19. Chronic ischemic heart disease: Treatment gaps <ul><li>Many patients have relative intolerances to maximum doses of traditional antianginal agents (  -blockers, CCBs, and nitrates) </li></ul><ul><li>Antianginal drugs without these limitations are needed </li></ul><ul><li>Patients continue to experience myocardial ischemia </li></ul><ul><li> -blockers and many CCBs have similar depressive hemodynamic and electrophysiologic effects </li></ul>
  20. 20. CAD: Multiple treatment options Reduce symptoms Treat underlying disease PCI & CABG Lifestyle intervention Alternative TX Medical therapy
  21. 21. Current antianginal strategies Current anti-anginal strategies Non pharmacologic Pharmacologic Trimetazidine Fasudil Nicorandil Ivabradine Ranolazine Exercise training EECP Chelation therapy SCS TMR
  22. 22. <ul><li>Exercise Training </li></ul><ul><li>Enhanced external counterpulsation (EECP) </li></ul><ul><ul><li> Endothelial function </li></ul></ul><ul><ul><li>Promotes coronary collateral formation </li></ul></ul><ul><ul><li> Peripheral vascular resistance </li></ul></ul><ul><ul><li> Ventricular function </li></ul></ul><ul><ul><li>Placebo effect </li></ul></ul><ul><li>Chelation therapy </li></ul>Current nonpharmacologic antianginal strategies <ul><li>Transmyocardial revascularization (TMR) </li></ul><ul><ul><li>Sympathetic denervation </li></ul></ul><ul><ul><li>Angiogenesis </li></ul></ul><ul><li>Spinal cord stimulation (SCS) </li></ul><ul><ul><li> Neurotransmission of painful stimuli </li></ul></ul><ul><ul><li> Release of endogenous opiates </li></ul></ul><ul><ul><li>Redistributes myocardial blood flow to ischemic areas </li></ul></ul>Allen KB et al. N Engl J Med. 1999;341:1029-36. Bonetti PO et al. J Am Coll Cardiol. 2003;41:1918-25. Murray S et al. Heart. 2000;83:217-20.
  23. 23. Potential cardioprotective benefits of exercise Domenech R. Circulation . 2006;113:e1-3. Kojda G et al. Cardiovasc Res . 2005;67:187-97. Shephard RJ et al. Circulation. 1999;99:963-72. NO production ROS generation ROS scavenging Other mechanisms Vasculature Thrombosis Myocardium
  24. 24. EECP - Enhanced External CounterPulsation <ul><li>External, pneumatic compression of lower extremities in diastole. </li></ul>
  25. 25. EECP - Enhanced External CounterPulsation
  26. 26. EECP - Enhanced External CounterPulsation <ul><li>Sequential inflation of cuffs </li></ul><ul><li>Retrograde aortic pressure wave </li></ul><ul><li>Increased Coronary perfusion pressure </li></ul><ul><li>Increased Venous Return </li></ul><ul><li>Increased Preload </li></ul><ul><li>Increased Cardiac Output </li></ul><ul><li>Simultaneous deflation of cuffs in late Diastole </li></ul><ul><li>Lowers Systemic Vascular Resistance </li></ul><ul><li>Reduced Preload </li></ul><ul><li>Decreased Cardiac workload </li></ul><ul><li>Decreased Oxygen Consumption </li></ul>
  27. 27. EECP - Enhanced External CounterPulsation <ul><li>35 total treatments </li></ul><ul><ul><li>5 days per week x 7 weeks </li></ul></ul><ul><ul><li>1 hour per day </li></ul></ul><ul><li>Appears to reduce severity of Angina </li></ul><ul><li>Not shown to improve survival or reduce myocardial infarctions </li></ul><ul><li>Indicated for CAD not amenable to revascularization </li></ul><ul><ul><li>Anatomy not amenable to procedures </li></ul></ul><ul><ul><li>High risk co-morbidities with excessive risk </li></ul></ul><ul><li>May be beneficial in treatment of refractory CHF too, but generally this is not an approved indication. </li></ul>
  28. 28. EECP – Contraindications & Precautions <ul><li>Arrhythmias that interfere with machine triggering </li></ul><ul><li>Bleeding diathesis </li></ul><ul><li>Active thrombophlebitis & severe lower extremity vaso-occlusive disease </li></ul><ul><li>Presence of significant AAA </li></ul><ul><li>Pregnancy </li></ul>
  29. 29. TMLR - Transmyocardial Laser Revascularization <ul><li>High power CO2 YAG and excimer laser conduits in myocardial to create new channels for blood flow </li></ul><ul><li>Possible explanations for effect </li></ul><ul><ul><li>Myocardial angiogenesis </li></ul></ul><ul><ul><li>Myocardial denervation </li></ul></ul><ul><ul><li>Myocardial fibrosis with secondary favorable remodeling </li></ul></ul>
  30. 30. TMLR – Direct Trial <ul><li>Only major blinded study </li></ul><ul><ul><li>298 pts with low dose, high dose, or no laser channels </li></ul></ul><ul><li>No benefit to TMLR vs Med therapy to </li></ul><ul><ul><li>Patient survival </li></ul></ul><ul><ul><li>Angina class </li></ul></ul><ul><ul><li>Quality of life assessment </li></ul></ul><ul><ul><li>Exercise duration </li></ul></ul><ul><ul><li>Nuclear perfusion imaging </li></ul></ul><ul><ul><li>Leon MB, et al. JACC 2005; 46:1812 </li></ul></ul><ul><li>High Surgical Risk (Mortality 5%) </li></ul><ul><li>Mainly used as adjunct therapy during CABG to treat myocardial that cannot be bypassed. </li></ul>
  31. 31. Chelation Therapy <ul><li>IV EDTA infusions </li></ul><ul><ul><li>30 treatments over about 3 months </li></ul></ul><ul><ul><li>Cost – about $3,000 </li></ul></ul><ul><ul><li>Aggressive marketing by 500 to 1000 physicians offering this treatment </li></ul></ul><ul><ul><li>PLACEBO effect only </li></ul></ul><ul><li>Claimed pathophysiologic effects </li></ul><ul><ul><li>Liberation of Calcium in plaque </li></ul></ul><ul><ul><li>Lower LDL, VLDL, and Iron stores </li></ul></ul><ul><ul><li>Inhibit platelet aggregation </li></ul></ul><ul><ul><li>Relax vasomotor tone </li></ul></ul><ul><ul><li>Scavenge “free radicals” </li></ul></ul>
  32. 32. Spinal Cord Stimulation Stimulation typically administered for 1-2 hrs tid Therapeutic mechanism appears to be alteration of anginal pain perception power source conducting wires electrodes at stimulation site
  33. 33. Long-term Outcomes Following SCS Prospective Italian Registry: 104 Patients, Follow-up 13.2 Mo Episodes/wk * p<0.0001 * * * * * * * (DiPede, et al. AJC 2003;91:951)
  34. 34. Randomized Trial of SCS vs. CABG For Patients with Refractory Angina Spinal cord stimulation (n=53) CABG (n=51) *P < 0.0001 * * * * (Mannheimer, et al. Circulation 1998;97:1157) 104 Patients with refractory angina, not suitable for PCI and high risk for re-op (3.2% of patients accepted for CABG) No difference in symptom relief between SCS and CABG
  35. 35. Current pharmacologic antianginal strategies <ul><li>New mechanistic approaches to angina </li></ul><ul><ul><li>Rho kinase inhibition ( fasudil ) </li></ul></ul><ul><ul><li>Metabolic modulation ( trimetazidine ) </li></ul></ul><ul><ul><li>Preconditioning ( nicorandil ) </li></ul></ul><ul><ul><li>Sinus node inhibition ( ivabradine ) </li></ul></ul><ul><ul><li>Late Na+ current inhibition ( ranolazine ) </li></ul></ul>
  36. 36. Rho kinase inhibition: Fasudil <ul><li>Rho kinase triggers vasoconstriction through accumulation of phosphorylated myosin </li></ul>Adapted from Seasholtz TM. Am J Physiol Cell Physiol . 2003;284:C596-8. Ca 2+ Ca 2+ PLC SR Ca 2+ Receptor Agonist Myosin Myosin-P Myosin phosphatase PIP 2 IP 3 MLCK VOC ROC Ca 2+ Calmodulin Rho Rho kinase Fasudil
  37. 37. Metabolic modulation (pFOX): Trimetazidine <ul><li>O2 requirement of glucose pathway is lower than FFA pathway </li></ul><ul><li>During ischemia, oxidized FFA levels rise, blunting the glucose pathway </li></ul>FFA Glucose Acyl-CoA Acetyl-CoA Pyruvate Energy for contraction Myocytes β -oxidation MacInnes A et al. Circ Res. 2003;93:e26-32. Lopaschuk GD et al. Circ Res. 2003;93:e33-7. Stanley WC. J Cardiovasc Pharmacol Ther . 2004;9(suppl 1):S31-45. pFOX = partial fatty acid oxidation FFA = free fatty acid Trimetazidine
  38. 38. Preconditioning: Nicorandil <ul><li>Nitrate-associated effects </li></ul><ul><li>Vasodilation of coronary epicardial arteries </li></ul><ul><li>Activation of ATP-sensitive K + channels </li></ul><ul><li>Ischemic preconditioning </li></ul><ul><li>Dilation of coronary resistance arterioles </li></ul>IONA Study Group. Lancet. 2002;359:1269-75. Rahman N et al. AAPS J . 2004;6:e34. N O O NO 2 HN
  39. 39. Sinus node inhibition: Ivabradine DiFrancesco D. Curr Med Res Opin. 2005;21:1115-22. SA = sinoatrial
  40. 40. Sinus node inhibition: Ivabradine DiFrancesco D. Curr Med Res Opin. 2005;21:1115-22. SA = sinoatrial SA node AV node Common bundle Bundle branches Purkinje fibers
  41. 41. Sinus node inhibition: Ivabradine <ul><li>I f current is an inward Na+/K+ current that activates pacemaker cells of the SA node </li></ul><ul><li>Ivabradine </li></ul><ul><ul><li>Selectively blocks I f in a current-dependent fashion </li></ul></ul><ul><ul><li>Reduces slope of diastolic depolarization, slowing HR </li></ul></ul>DiFrancesco D. Curr Med Res Opin. 2005;21:1115-22. 40 20 0 – 20 – 40 – 60 0.5 Potential (mV) Control Ivabradine 0.3 µM Time (seconds) SA = sinoatrial
  42. 42. Myocardial ischemia causes enhanced late INa Na + Impaired Inactivation Na + Ischemia Adapted from Belardinelli L et al. Eur Heart J Suppl. 2006;(8 suppl A):A10-13 . Belardinelli L et al. Eur Heart J Suppl . 2004;6(suppl I):I3-7. Sodium Current 0 Late Peak 0 Late Peak Sodium Current
  43. 43. Late Na+ current inhibition: Ranolazine Belardinelli L et al. Eur Heart J Suppl . 2006;8(suppl A):A10-13. Belardinelli L et al. Eur Heart J Suppl . 2004;(6 suppl I):I3-7. Myocardial ischemia  Late I Na Na + Overload Ca 2+ Overload Mechanical dysfunction  LV diastolic tension  Contractility Electrical dysfunction Arrhythmias Ranolazine
  44. 44. Understanding Angina at the Cellular Level <ul><li>Ischemia impairs cardiomyocyte sodium channel function </li></ul><ul><li>Impaired sodium channel function leads to: </li></ul><ul><ul><li>Pathologic increased late sodium current </li></ul></ul><ul><ul><li>Sodium overload </li></ul></ul><ul><ul><li>Sodium-induced calcium overload </li></ul></ul><ul><li>Calcium overload causes diastolic relaxation failure, which: </li></ul><ul><ul><li>Increases myocardial oxygen consumption </li></ul></ul><ul><ul><li>Reduces myocardial blood flow and oxygen supply </li></ul></ul><ul><ul><li>Worsens ischemia and angina </li></ul></ul>Ischemia ↑ Late I Na Na + Overload Diastolic relaxation failure Extravascular compression Ca ++ Overload Chaitman BR. Circulation. 2006;113:2462-2472 Ranolazine
  45. 45. Na+/Ca2+ overload and ischemia Adapted from Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13.  Late Na + current  Diastolic wall tension (stiffness) Intramural small vessel compression (  O 2 supply)  O 2 demand Na + overload Ca 2+ overload Myocardial ischemia
  46. 46. Ranolazine Ischaemia (  oxygen supply/  Demand) <ul><li> late Na + current </li></ul><ul><li> Na + /Ca ++ exchange pump activation </li></ul>[Ca 2+ ] overload  Diastolic wall tension (stiffness)  Vascular compression  [Na + ] i
  47. 47. Ranolazine – hemodynamic affects <ul><li>No affect of Blood Pressure or Heart Rate </li></ul><ul><li>Can be added to Conventional Medical therapy, especially when BP and HR do not allow further increase in dose of BetaBlockers, Ca Channel blockers, and Long Acting Nitrates. </li></ul><ul><li>Ranolazine has twin pronged action. </li></ul><ul><ul><li>pFOX </li></ul></ul><ul><ul><li>Late Na inward entry blockade </li></ul></ul>
  48. 48. Metabolic modulation (pFOX) and ranolazine <ul><li>Clinical trials showed ranolazine SR 500–1000 mg bid (~2–6 µmol/L) reduced angina </li></ul><ul><li>Experimental studies demonstrated that ranolazine 100 µmol/L achieved only 12% pFOX inhibition </li></ul><ul><ul><li>Ranolazine does not inhibit pFOX substantially at clinically relevant doses </li></ul></ul><ul><li>Fatty acid oxidation Inhibition is not a major antianginal mechanism for ranolazine </li></ul>MacInnes A et al. Circ Res. 2003;93:e26-32. Antzelevitch C et al. J Cardiovasc Pharmacol Therapeut . 2004;9(suppl 1):S65-83. Antzelevitch C et al. Circulation . 2004;110:904-10. pFOX = partial fatty acid oxidation
  49. 49. Ranolazine: Key concepts <ul><li>Ischemia is associated with ↑ Na+ entry into cardiac cells </li></ul><ul><ul><li>Na+ efflux by Na+/Ca2+ exchange results in ↑ cellular [Ca2+]i and eventual Ca2+ overload </li></ul></ul><ul><ul><li>Ca2+ overload may cause electrical and mechanical dysfunction </li></ul></ul><ul><li>↑ Late INa is an important contributor to the [Na+]i - dependent Ca2+ overload </li></ul><ul><li>Ranolazine reduces late INa </li></ul>Belardinelli L et al. Eur Heart J Suppl . 2006;8(suppl A):A10-13. Belardinelli L et al. Eur Heart J Suppl . 2004;(6 suppl I):I3-7.
  50. 50. Na+ and Ca2+ during ischemia and reperfusion Tani M and Neely JR. Circ Res. 1989;65:1045-56. Na + ( μ mol/g dry) Ca 2+ ( μ mol/g dry) Time (minutes) Rat heart model Intracellular levels Ischemia Reperfusion 90 60 30 0 12 8 4 0 0 10 20 30 40 50 60
  51. 51. Pharmacologic Classes for Treatment of Angina Reduced Cardiac Stiffness O O Ranolazine Vaso-dilitation Nitrates Decrease Pump function + Vaso-dilitation Calc Channel Blockers Decrease pump function Beta Blockers Physiologic Mechanism Impact on BP Impact on HR Medication Class
  52. 52. Late Na+ accumulation causes LV dysfunction Fraser H et al. Eur Heart J. 2006. Isolated rat hearts treated with ATX-II, an enhancer of late I Na LV dP/dt (mm Hg/sec, in thousands) LV-dP/dt LV+dP/dt (-) (+) Time (minutes) ATX-II 12 nM (n = 13) ATX-II Ranolazine 8.6 µM (n = 6) Ranolazine -4 -3 -2 -1 0 1 2 3 4 5 6 10 20 30 40 50
  53. 53. Late INa blockade - blunts experimental ischemic LV damage LV end diastolic pressure Baseline 15 30 45 60 0 10 20 30 40 50 60 70 Vehicle (n = 10) Ranolazine 10 µM (n = 7) * * Reperfusion time (minutes) mm Hg LV -dP/dt (Relaxation) Belardinelli L et al. Eur Heart J Suppl . 2004;6(suppl I):I3-7. Gralinski MR et al. Cardiovasc Res. 1994;28:1231-7. *P < 0.05 Vehicle Ranolazine Baseline 30 60 75 90 -1000 -800 -600 -400 -200 0 * * * * mm Hg/sec Reperfusion time (minutes) Vehicle (n = 12) Ranolazine 5.4 µM (n = 9) Isolated rabbit hearts
  54. 54. Myocardial ischemia: Sites of action of anti-ischemic medication Ca 2+ overload Electrical instability Myocardial dysfunction ( ↓ systolic function/ ↑ diastolic stiffness) ↑ O 2 Demand Heart rate Blood pressure Preload Contractility ↓ O 2 Supply Traditional anti-ischemic medications: β -blockers Nitrates Ca 2+ blockers Courtesy of PH Stone, MD and BR Chaitman, MD. 2006. Consequences of ischemia Ischemia Development of ischemia Ranolazine
  55. 55. Summary <ul><li>Ischemic heart disease is a prevalent clinical condition </li></ul><ul><li>Improved understanding of ischemia has prompted new therapeutic approaches </li></ul><ul><ul><li>Rho kinase inhibition </li></ul></ul><ul><ul><li>Metabolic modulation </li></ul></ul><ul><ul><li>Preconditioning </li></ul></ul><ul><ul><li>Inhibition of I f and late INa currents </li></ul></ul>
  56. 56. Summary <ul><li>Late INa inhibition and metabolic modulation reduce angina with minimal or no pathophysiologic effects </li></ul><ul><ul><li>Mechanisms of action is complementary to traditional agents </li></ul></ul>
  57. 57. Stable CAD: Multiple treatment options Reduce symptoms Treat underlying disease PCI & CABG Lifestyle intervention Alternative TX Medical therapy
  58. 58. ECG R Q T U P S mV + - P Wave Space QRS ST T PQ

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