The document discusses refractory angina, a condition where chest pain persists despite optimal medical therapy and invasive procedures. It describes various treatment options for chronic angina when standard therapies fail, including ranolazine which inhibits the late sodium current as a new potential antianginal option.

1. Refractory angina: The scope for ranolazine. Dr. B. K. Iyer

2. Chronic / Refractory angina What is this condition? It is the disabling chest pain that persists Despite lifestyle adjustment and Despite optimal medical therapy and Despite invasive coronary interventions.

3. Correlation - symptom severity and ischaemic burden 1. Pain out of proportion to ischaemia 20% of patients undergoing angiography because of angina have normal coronary arteries 2. Ischaemia with no pain 70% ischaemic episodes in the community are silent 25% of infarcts are silent 3. No significant differences in objective measures of ischaemia between patients with angina and silent ischaemics Klein et al. Circulation 1994;89:1958-66 See also Warren J. NEJMS 1812;1:1-11

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. 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. Angina Pectoris - Understanding the options when Standard Therapy Fails Dr. B. K. Iyer

7. Basis Patients experience angina despite medical therapy & / or revascularization Clinical variations in broad range of patients unresponsive to current treatment options Elderly Diabetes LV dysfunction or heart failure Late Na + blockade is a potentially effective new antianginal option with a mechanism of action complementary to traditional agents

8. CAD: Multiple treatment options Reduce symptoms Treat underlying disease Lifestyle intervention Alternative TX Medical therapy PCI & CABG

9. CAD: Multiple treatment options Reduce symptoms Treat underlying disease PCI & CABG Lifestyle intervention Alternative TX Medical therapy

10. Invasive Treatment of CAD Acute Coronary Syndrome and Acute MI Aggressive treatment unquestionably shown to save lives and reduce future MIs. Stable Angina Pectoris What is the role of Coronary Revascularization ? CABG is better than Medical Therapy for 3 vessel disease CAD that involves Prox LAD (European Coronary Surgery Study) 3 vessel CAD with low EF (CASS)

11. PCI in chronic angina and stable CAD PCI improves angina and exercise capacity However, compared to optimal medical therapy, does PCI Prolong survival? Reduce risk of subsequent MI? Reduce hospitalization for unstable angina? Decrease need for subsequent CABG? Improve quality of life?

12. 55 yr old female with stable angina

13. Revascularization for Stable CAD Acute Coronary Syndrome and Acute MI Clearly shown to improve survival Chronic Stable Angina Goal may be to just reduce symptoms and improve quality of life 1 year after PCI or CABG 25 to 60% of patients still have ongoing angina Many patients are deemed “inoperable” Condition not suitable for PCI or CABG Co-morbidities make procedure too high risk Benefit Risk

14. CAD: Multiple treatment options Reduce symptoms Treat underlying disease PCI & CABG Lifestyle intervention Alternative TX Medical therapy

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. 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. CAD: Multiple treatment options Reduce symptoms Treat underlying disease PCI & CABG Lifestyle intervention Alternative TX Medical therapy

18. Chronic CAD – Conventional Medical therapy Decrease Myocardial Oxygen demand Decrease in HR (Beta blockers and some Calcium Channel Blockers) Decrease in Myocardial Contractility (BB and some CCBs) Increase Oxygen supply Long Acting Nitrates Calcium Channel Blockers

19. Chronic ischemic heart disease: Treatment gaps Many patients have relative intolerances to maximum doses of traditional antianginal agents (  -blockers, CCBs, and nitrates) Antianginal drugs without these limitations are needed Patients continue to experience myocardial ischemia  -blockers and many CCBs have similar depressive hemodynamic and electrophysiologic effects

20. CAD: Multiple treatment options Reduce symptoms Treat underlying disease PCI & CABG Lifestyle intervention Alternative TX Medical therapy

21. Current antianginal strategies Current anti-anginal strategies Non pharmacologic Pharmacologic Trimetazidine Fasudil Nicorandil Ivabradine Ranolazine Exercise training EECP Chelation therapy SCS TMR

22. Exercise Training Enhanced external counterpulsation (EECP)  Endothelial function Promotes coronary collateral formation  Peripheral vascular resistance  Ventricular function Placebo effect Chelation therapy Current nonpharmacologic antianginal strategies Transmyocardial revascularization (TMR) Sympathetic denervation Angiogenesis Spinal cord stimulation (SCS)  Neurotransmission of painful stimuli  Release of endogenous opiates Redistributes myocardial blood flow to ischemic areas 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. 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. EECP - Enhanced External CounterPulsation External, pneumatic compression of lower extremities in diastole.

25. EECP - Enhanced External CounterPulsation

26. EECP - Enhanced External CounterPulsation Sequential inflation of cuffs Retrograde aortic pressure wave Increased Coronary perfusion pressure Increased Venous Return Increased Preload Increased Cardiac Output Simultaneous deflation of cuffs in late Diastole Lowers Systemic Vascular Resistance Reduced Preload Decreased Cardiac workload Decreased Oxygen Consumption

27. EECP - Enhanced External CounterPulsation 35 total treatments 5 days per week x 7 weeks 1 hour per day Appears to reduce severity of Angina Not shown to improve survival or reduce myocardial infarctions Indicated for CAD not amenable to revascularization Anatomy not amenable to procedures High risk co-morbidities with excessive risk May be beneficial in treatment of refractory CHF too, but generally this is not an approved indication.

28. EECP – Contraindications & Precautions Arrhythmias that interfere with machine triggering Bleeding diathesis Active thrombophlebitis & severe lower extremity vaso-occlusive disease Presence of significant AAA Pregnancy

29. TMLR - Transmyocardial Laser Revascularization High power CO2 YAG and excimer laser conduits in myocardial to create new channels for blood flow Possible explanations for effect Myocardial angiogenesis Myocardial denervation Myocardial fibrosis with secondary favorable remodeling

30. TMLR – Direct Trial Only major blinded study 298 pts with low dose, high dose, or no laser channels No benefit to TMLR vs Med therapy to Patient survival Angina class Quality of life assessment Exercise duration Nuclear perfusion imaging Leon MB, et al. JACC 2005; 46:1812 High Surgical Risk (Mortality 5%) Mainly used as adjunct therapy during CABG to treat myocardial that cannot be bypassed.

31. Chelation Therapy IV EDTA infusions 30 treatments over about 3 months Cost – about $3,000 Aggressive marketing by 500 to 1000 physicians offering this treatment PLACEBO effect only Claimed pathophysiologic effects Liberation of Calcium in plaque Lower LDL, VLDL, and Iron stores Inhibit platelet aggregation Relax vasomotor tone Scavenge “free radicals”

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. 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. 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. Current pharmacologic antianginal strategies New mechanistic approaches to angina Rho kinase inhibition ( fasudil ) Metabolic modulation ( trimetazidine ) Preconditioning ( nicorandil ) Sinus node inhibition ( ivabradine ) Late Na+ current inhibition ( ranolazine )

36. Rho kinase inhibition: Fasudil Rho kinase triggers vasoconstriction through accumulation of phosphorylated myosin 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. Metabolic modulation (pFOX): Trimetazidine O2 requirement of glucose pathway is lower than FFA pathway During ischemia, oxidized FFA levels rise, blunting the glucose pathway 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. Preconditioning: Nicorandil Nitrate-associated effects Vasodilation of coronary epicardial arteries Activation of ATP-sensitive K + channels Ischemic preconditioning Dilation of coronary resistance arterioles IONA Study Group. Lancet. 2002;359:1269-75. Rahman N et al. AAPS J . 2004;6:e34. N O O NO 2 HN

39. Sinus node inhibition: Ivabradine DiFrancesco D. Curr Med Res Opin. 2005;21:1115-22. SA = sinoatrial

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. Sinus node inhibition: Ivabradine I f current is an inward Na+/K+ current that activates pacemaker cells of the SA node Ivabradine Selectively blocks I f in a current-dependent fashion Reduces slope of diastolic depolarization, slowing HR 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. 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. 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. Understanding Angina at the Cellular Level Ischemia impairs cardiomyocyte sodium channel function Impaired sodium channel function leads to: Pathologic increased late sodium current Sodium overload Sodium-induced calcium overload Calcium overload causes diastolic relaxation failure, which: Increases myocardial oxygen consumption Reduces myocardial blood flow and oxygen supply Worsens ischemia and angina Ischemia ↑ Late I Na Na + Overload Diastolic relaxation failure Extravascular compression Ca ++ Overload Chaitman BR. Circulation. 2006;113:2462-2472 Ranolazine

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. Ranolazine Ischaemia (  oxygen supply/  Demand)  late Na + current  Na + /Ca ++ exchange pump activation [Ca 2+ ] overload  Diastolic wall tension (stiffness)  Vascular compression  [Na + ] i

47. Ranolazine – hemodynamic affects No affect of Blood Pressure or Heart Rate 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. Ranolazine has twin pronged action. pFOX Late Na inward entry blockade

48. Metabolic modulation (pFOX) and ranolazine Clinical trials showed ranolazine SR 500–1000 mg bid (~2–6 µmol/L) reduced angina Experimental studies demonstrated that ranolazine 100 µmol/L achieved only 12% pFOX inhibition Ranolazine does not inhibit pFOX substantially at clinically relevant doses Fatty acid oxidation Inhibition is not a major antianginal mechanism for ranolazine 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. Ranolazine: Key concepts Ischemia is associated with ↑ Na+ entry into cardiac cells Na+ efflux by Na+/Ca2+ exchange results in ↑ cellular [Ca2+]i and eventual Ca2+ overload Ca2+ overload may cause electrical and mechanical dysfunction ↑ Late INa is an important contributor to the [Na+]i - dependent Ca2+ overload Ranolazine reduces late INa 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. 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. 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. 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. 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. 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. Summary Ischemic heart disease is a prevalent clinical condition Improved understanding of ischemia has prompted new therapeutic approaches Rho kinase inhibition Metabolic modulation Preconditioning Inhibition of I f and late INa currents

56. Summary Late INa inhibition and metabolic modulation reduce angina with minimal or no pathophysiologic effects Mechanisms of action is complementary to traditional agents

57. Stable CAD: Multiple treatment options Reduce symptoms Treat underlying disease PCI & CABG Lifestyle intervention Alternative TX Medical therapy

58. ECG R Q T U P S mV + - P Wave Space QRS ST T PQ