1. Dr Julian Johny Thottian

2. INTRODUCTION Chronic angina is a condition that impairs quality of life and is associated with decreased life expectancy Cardiac metabolism- LCFAs are the major source of energy (80%) and Glucose (20%) in aerobic conditions. In fetus, the main source of energy is glucose and shift to FFA is in the early post natal period.

3. Cardiac metabolism

4. Current therapies that reduce angina frequency and increase the threshold at which demand-induced myocardial ischemic symptoms become evident include : Drugs :Nitrates, β-blockers, Calcium antagonist Exercise conditioning Enhanced External Counterpulsation Coronary revascularization

5. Current antianginal strategies Current anti-anginal strategies Non pharmacologic Pharmacologic Trimetazidine Fasudil Nicorandil Ivabradine Ranolazine Exercise training EECPChelationtherapy SCS TMR

8. Consequences associated with dysfunction of late sodium current Diseases (eg, ischemia, heart failure) Pathological milieu (reactive O 2 species, ischemic metabolites) Toxins and drugs (eg, ATX-II, etc.) Na + channel (Gating mechanism malfunction) Increase ATP consumption Decrease ATP formation Oxygen supply and demand Abnormal contraction and relaxation ↑ diastolic tension ( ↑ LV wall stiffness) Mechanical dysfunction Early after potentials Beat-to-beat Δ APD Arrhythmias (VT) Electrical instability

9. Diastolic relaxation failure increases oxygen consumption and reduces oxygen supply Increased myocardial tension during diastole: Increases myocardial O 2 consumption Compresses intramural small vessels Reduces myocardial blood flow Worsens ischemia and angina

10. Advances 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

11. Ranolazine (N-(2,6-dimethyphenyl)-4-[2-hydroxy-3- (2-methoxyphenoxy)-propyl]-1-piperazineacetamide) is a substituted piperazine compound. pFOX inhibitor -that ranolazine only inhibits fatty- acid oxidation during the periods of elevated plasma FFA levels associated with myocardial ischaemia Late sodium current blocker

12. Understanding Angina at the Cellular Level Ischemia impairs cardiomyocyte sodium channel function Ischemia impairs cardiomyocyte sodium channel function Impaired sodium channel function leads to: Impaired sodium channel function leads to: Pathologic increased late sodium current Pathologic increased late sodium current Sodium overload Sodium overload Sodium-induced calcium overload Sodium-induced calcium overload Calcium overload causes diastolic relaxation failure, which: Calcium overload causes diastolic relaxation failure, which: Increases myocardial oxygen consumption Increases myocardial oxygen consumption Reduces myocardial blood flow and oxygen supply Reduces myocardial blood flow and oxygen supply Worsens ischemia and angina Worsens ischemia and angina Ranolazine Ischemia ↑ Late I Na Na + Overload Diastolic relaxation failure Extravascular compression Ca ++ Overload Chaitman BR. Circulation. 2006;113:2462-2472

13. 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

14. Sodium Current 0 Late Peak 0 Late Peak Sodium Current Na + ImpairedInactivationImpairedInactivation Ischemia Myocardial ischemia causes enhanced late INa 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.

16. 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. 1. pFOX 2. Late Na inward entry blockade

17. 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

18. Medication Class Impact on HR Impact on BP Physiologic Mechanism Beta Blockers Decrease pump function Calc Channel Blockers Decrease Pump function + Vaso- dilitation NitratesVaso-dilitation RanolazineOO Reduced Cardiac Stiffness Pharmacologic Classes for Treatment of Angina

19. Myocardial ischemia: Sites of action of anti-ischemic medication Consequences of ischemia Ca 2+ overload Electrical instability Myocardial dysfunction ( ↓ systolic function/ ↑ diastolic stiffness) Ischemia ↑ O 2 Demand Heart rate Blood pressure Preload Contractility ↓ O 2 Supply Development of ischemia Traditional anti-ischemic medications: β-blockers Nitrates Ca 2+ blockers Courtesy of PH Stone, MD and BR Chaitman, MD. 2006. Ranolazine

20. 3 ranolazine trials

21. Baseline characterstics

25. NO MUCH BENEFIT IN ACS

26. Contraindications Ranolazine is known to increase the QT interval on the electrocardiogram. Mean increase in the corrected QT interval (QTc) is approximately 6 msec, about 5% of individuals may have QTc prolongations of 15 msec or longer. (MARISA) It blocks Ikr and hence prolongs the QT interval. Clinical experience in coronary syndrome population did not show an increased risk of proarrhythmia or sudden death Strong CYP3A4 inhibitors and drug that interact with P glycoprotein

27. Contd… Used with caution with other CYP3A4 inhibitors and also drugs that prolong QT. INTERACTS with Digoxin, simvastatin,cyclosporine, diltiazem, verapamil, ketoconazole, macrolides, grape fruit juice

28. Other beneficial effects US FDA has granted permission for- HbA1c reduction in coronary artery disease patients with diabetes and antiarrhythmic benefits according to the results of MERLIN TIMI 36 trial. Uses in heart failure and neuropathic pain are being studied extensively.

29. Side effects The most common adverse events that led to discontinuation placebo were Dizziness (1.3% versus 0.1%) Nausea (1% versus 0%) Asthenia, Constipation Headache (each about 0.5% versus 0%). Doses above 1000 mg twice daily are poorly tolerated. Conclusions from CARISA MARISA & ERICA

30. Sinus node inhibition: Ivabradine DiFrancesco D. Curr Med Res Opin. 2005;21:1115-22. IVABRADINE SA node AV node Common bundle Bundle branches Purkinje fibers

31. 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 depolarization, slowing HR DiFrancesco D. Curr Med Res Opin. 2005;21:1115-22. 40 20 0 –20 –40 –60 0.5 Potential (mV) ControlIvabradine 0.3 µM Time (seconds)

32. Trials associated It produces similar effects to those of atenolol, as measured in the randomized double-blind INITIATIVE trial, which compared ivabradine (5, 7.5 and 10 mg bid) with atenolol at doses of 50 and 100 mg per day and found to be non inferior. It is safe agent and no changes in QT interval. ASSOCIATE Trial is double blind RCT done on 889 patients which found that ivabradine was better than placebo in anti anginal and anti ischaemic efficacy. Combination of this drug and betablockers was definitely effective without untoward effects.

33. BEAUTifUL TRIAL-post hoc analysis The BEAUTIFUL investigators sought to analyze, post hoc, the effect of ivabradine on patients with limiting angina at baseline within the BEAUTIFUL trial. Patients with limiting angina -13.8% of the trial population. 24% reduction in the primary endpoint [cardiovascular mortality or hospitalization for fatal and non-fatal myocardial infarction (MI) or heart failure HR, 0.76; 95% CI, 0.58–1.00] and a 42% reduction in hospitalization for MI (HR, 0.58; 95% CI, 0.37– 0.92). In patients with heart rate ≥70 bpm, there was a 73% reduction in hospitalization for MI (HR, 0.27; 95% CI, 0.11–0.66) and a 59% reduction in coronary revascularization (HR, 0.41; 95% CI, 0.17– 0.99). These results indicate that ivabradine is most helpful to reduce adverse cardiac events in patients with limiting angina and that in this population, its benefit may extend well beyond symptom control.

34. Side effect /effects Blurring of vision No QT prolongation No negative inotropic properties Improvements in exercise tolerance and prevention of exercise-induced ischaemia

35. 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 Trimetazidine 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

36. It is piperazine derivative (1-[2,3,4-trimethoxibenzyl)]- piperazine). Launched as a cytoprotective agent. No significant negative inotropic or vasodilator properties either at rest or during dynamic exercise TRIMPOL II –RCT of 426 patients with CSA who were randomised to either trimetazidine 20 mg three times a day or placebo in addition to metoprolol 50mg. This study demonstrated an improvement in time to STsegment depression on exercise tolerance testing (ETT), total exercise workload, mean nitrate consumption, and angina frequency in patients randomised to receive trimetazidine

37. Large multicentric trial of 19000 patients post MI by EMIP-FR group showed no benefit of iv infusion of trimetazidine immediately post MI over 48hrs MOA – CPT -1 inhibitor and also acts in inhibition of the enzyme long-chain 3-ketoacyl coenzyme A thiolase (LC 3- KAT)[Kantor et al] VASCO,largest RCT, showed no benefit as an add on in angina Safety issues and adverse effects ?????

38. Side effects Extrapyramidal and parkinsonian symptoms recently published by EMA 2012 Restless leg syndrome. Use is limited in severe renal impairment.

39. Perhexilene Earlier designed as a CCB but doesnot act like a CCB It doesnot affect the heart rate or SVR Multiple randomised trials show that it has anti anginal effect as monotherapy or as combination. Inhibition of CPT-1 and, to a lesser extent, CPT-2, resulting in increased glucose and lactate utilisation S/E hepatotoxicity and peripheral neuropathy due to phospholipid accumulation as a result of CPT ½ inhibition.

40. Cole et al confirmed the safety of perhexiline in a randomised, double-blind, crossover study following initiation of 100 mg of perhexiline BD with subsequent plasma-guided dose titration; none of the developed the dreaded side effects. Other s/e nausea,dizziness and hypoglycaemia Other uses – symptomatic aortic stenosis Circulation 1990;81(4):1260–70

41. Etomoxir/ Oxfenicine Potential anti anginal agent Launched as an anti diabetic agent due to hypoglycaemic effects CPT 1 INHIBITOR Improvement in LV function in rats- Turcani & Rupp Single study available on humans (15 patients) with NYHA II – III Etomoxir 80mg was administered.\ Only animal studies on oxfenicine.

42. 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

43. DOSAGE- 20mg bid Tolerance is seen with chronic dosage No cross tolerance with nitrates The Impact Of Nicorandil in Angina (IONA) trial showed a significant reduction of major coronary events in stable angina patients treated with nicorandil compared with placebo as add-on to conventional therapy Also used in unstable angina. It also reduces the number of further attacks Additive effects with nitrates

44. 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+ PLC SR Ca 2+ Receptor Agonist Myosin Myosin-P Myosin phosphatase PIP 2 IP 3 MLCK VOCROC Ca 2+ Calmodulin Rho Rho kinase Fasudil

45. Fasudil up to 80 mg three times daily significantly increased the ischemic threshold of angina patients during exercise with a trend toward increased exercise duration. Double-Blind, Placebo-Controlled, Phase 2 Trial on 84 patients J Am Coll Cardiol. 2005;46(10):1803-1811

46. Molsodomine & linsodomine Anti anginal and anti ischaemic Acts like nitrates Metabolises in liver to form linsodomine Orally active Metabolised in liver

47. TMLR Surgical surgeons use the laser to make holes between 20 and 40 tiny (one-millimeter-wide) Surgical incision made Done along with CABG sometimes

50. Percutaneous TMR

51. Rationale Improved perfusion by stimulation of angiogenesis Potential placebo effect Anesthetic effect mediated by the destruction of sympathetic nerves carrying pain-sensitive afferent fibers Peri-procedural infarction.

52. 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 remodelling

53. 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%) High Surgical Risk (Mortality 5%) Mainly used as adjunct therapy during CABG to treat myocardial that cannot be bypassed. Mainly used as adjunct therapy during CABG to treat myocardial that cannot be bypassed.

54. EECP

55. EECP Increases arterial blood pressure and retrograde aortic blood flow during diastole (diastolic augmentation). Cuffs are wrapped around the patients legs and sequential pressure (300mmHg) is applied in early diastole. 3 pairs of cuffs

56. Patient selection Angina class III/IV Refractory to medical therapy Reversible ischemia of the free wall not amenable for revascularization Excluded if LVEF<20% or had current major illness

57. EECP - Enhanced External CounterPulsation External, pneumatic compression of lower extremities in diastole.

58. EECP - Enhanced External CounterPulsation

59. 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 Lowers Systemic Vascular Resistance Reduced afterload Reduced afterload Decreased Cardiac workload Decreased Cardiac workload Decreased Oxygen Consumption Decreased Oxygen Consumption

60. 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.

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

62. MUST EECP Blinded RCT on 139 patients to check the safety and efficacy of EECP Patients with CSA were given 35hrs of EECP/WK Exercise duration increased. Time to ≥1-mm ST- segment depression increased significantly. Patients saw a decrease in angina episodes (p < 0.05). Nitroglycerin usage decreased.

63. 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 Claimed pathophysiologic effects Liberation of Calcium in plaque Liberation of Calcium in plaque Lower LDL, VLDL, and Iron stores Lower LDL, VLDL, and Iron stores Inhibit platelet aggregation Inhibit platelet aggregation Relax vasomotor tone Relax vasomotor tone Scavenge “free radicals” Scavenge “free radicals”

65. Spinal Cord Stimulation power sourceconducting wires electrodes at stimulation site Stimulation typically administered for 1-2 hrs tid Therapeutic mechanism appears to be alteration of anginal pain perception

66. Long-term Outcomes Following SCS Prospective Italian Registry: 104 Patients, Follow-up 13.2 Months Episodes/wk * p<0.0001 * * * ** * * (DiPede, et al. AJC 2003;91:951)

67. 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

68. 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 VasculatureThrombosisMyocardium

69. THANK YOU

70. BOOK REFERENCES Braunwald`s heart diseases -9 th edition- Unit 7 Chapt-57 Cardiovascular medicine 3 rd edition –Brian Griffin- Section-1 Chapt-5 Hurst-The Heart -13 th edition. Part 8 Chapt-54 Harrisons Principles of internal medicine –18 th edition Part 10 Section 5 Chapt-243 US FDA APPROVAL OF RANOLAZINE 2008

71. REFERENCES Ju YK, Saint DA, Gage PW. Hypoxia increases persistent sodium current in rat ventricular myocytes. J Physiol. 1996;497 ( Pt 2):337-347. Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13 PH Stone, MD and BR Chaitman, MD. 2006 DiPede, et al. AJC 2003;91:951 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 Mannheimer, et al. Circulation 1998;97:1157 Leon MB, et al. JACC 2005; 46:1812 Circulation 1990;81(4):1260–70 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 Chaitman et al JAMA 2004; 43: 1375 PH Stone Circulation 2005;11

73. Question 1 All are partial fatty acid oxidase inhibitors except? a) Fasudil b) Trimetazidine c) Etomoxir d) Oxfenicine

74. Question 2 a) IONA trial proves efficacy of nicorandil in ACS b) Activation of ATP-sensitive K + channels c) Helps in Ischemic preconditioning d) Dilation of coronary resistance arterioles e) Vasodilation of coronary epicardial arteries

75. Question 3 False statement regarding ischaemia at cellular level a) Calcium overload b) Sodium overload c) Decreased late sodium current d) Increased early after potentials

76. Question 4 False regarding ranolazine trials a) CARISA- ranolazine as an adjunct with other anti anginals b) MARISA- effect of various doses of ranolazine as monotherapy compared with placebo c) ERICA- effect of ranolazine with amlodipine d) ASSOCIATE – ranolazine in ACS patients

77. Question 5 True about ranolazine are all except a) Does not affect double product b) Decrease diastolic stiffness c) Blockade of Late sodium current d) Prolongs QT interval e) Decrease Hb A1C levels

78. Question 6 False regarding TMR a) Improved perfusion by stimulation of angiogenesis b) Potential placebo effect c) Anesthetic effect mediated by the destruction of sympathetic nerves carrying pain-sensitive afferent fibers d) Free radical scavenging

79. Question 7 False regarding EECP a) Sequential inflation and simultaneous deflation b) MUST EECP shows definite benefit in decreasing angina c) Contraindicated in pregnancy d) Can be done in those with EF < 20%

80. Question 8 False about ivabradine a) INITIATIVE trial compared ivabradine with betablockers b) ASSOCIATE trial compares ivabradine with placebo and found it definitely better AND also found beneficial when combined with beta blockers c) Prolongs QT interval d) Beautiful Trial proved the anti anginal efficacy of ivabradine.

81. Question 9 False about SCS a) Stimulates spinal cord at level C7-T4 b) No added benefits when compared to CABG c) Mechanism of action is pain modification by gate control mechanism. d) Eddicks et al proved it to be more beneficial than TLR

82. Question 10 Which is a false match a) IONA – NICORANDIL b) TRIMPOL – MOLSODOMINE c) MERLIN TIMI 36- RANOLAZINE d) ASSOCIATE – IVABRADINE