Nuevas perspectivas en el tratamiento de la angina crónica estable. Congreso de las Enfermedades Cardiovasculares 2009. 22/10/2009 Barcelona Sociedad Española de Cardiología

1. Nu evas perspectivas en el tratamiento de la angin a crónica estable Juan Tamargo Departamento de Farmacología, Facultad de Medicina Universidad Complutense, Madrid. Spain

4. New mechanistic approaches to myocardial ischemia Sinus node inhibition (IVABRADINE) Late I Na inhibition (Ranolazine) Rho kinase inhibition (fasudil) Metabolic modulation (trimetazidine) Preconditioning (nicorandil) O H 3 C O H 3 C O N CH 3 O CH 3 O CH 3 O O NO 2 H N N N N O N CH 3 H CH 3 CH 3 O O H N SO 2 NH N O OH CH 3 CH 3 OCH 3 H N N N O

6. -50 -50 50 0 mV -50 -50 pA I f I f I CaT I CaL I K Potenciales de acción registrados en el nodo SA (A) y en miocitos ventriculares (B) PU PDM

8. Cardiopatía Isquémica Inhibir la  -oxidación de los ácidos grasos, aumentar la oxidación de la glucosa Trimetazidina Oxfenicina Etoxomir Perhexilina S-15176

11. Coraboeuf et al. Am J Physiol 1979;236:H561-H567 “ They shortening was due to a TTX-sensitive Na + current flowing during the plateau of the action potential” “ This current flows through a small proportion of Na+ channels with no inactivation mechanism (or inactivation different from normal), e.g. the late I na Tetrodotoxin prolongs the APD in Purkinje fibers at concentrations lower than those at which it inhibited the I Na 1: control. 2: TTX (0.03  M) Late I Na

13. Gating modes in cardiac Na + channels (Nav1.5  subunit) expressed in HEK cells Late I Na results from two types of channel activity: scattered late openings and burst openings Undrovinas et al. J Mol Cell Cardiol 2002; 34:1477-1489

16. Murphy E. et al. Physiology 2008;23:115-123 2008 Representative changes in Na, Ca, Mg, ATP, PCr, and pH during ischemia

17. A pathological paradigm NaCh inactivation failure Ischemia Ca 2+ Overload  late I Na  Na + i NCX

20. Transmural heterogeneity of late I Na Late I Na is more prominent in M and Purkinje cells Zygmunt et al. Am J Physiol 2001;281:H689-H697 Pathological Iate I Na increases the dispersion of ventricular repolarization, may trigger early afterdepolarizations and lead to reentrant excitation Endo M cell Epi ECG

21. Consequences of increasing the late I Na Leading to QT prolon ga tion, EADs and beat-to-beat variation in APD Song et al. J Cardiovasc Pharmacol 2004; Maltsev et al. Eur J Heart Fail 2007 Human failing heart Cardiac myocytes exposed to ATX-II

22. Abnormal Late I Na Prolongs APD (QTc), induced EADs and delayed relaxation Na + in out Na + Channel Na v 1.5 Sodium Current Action Potential 0 Late I Na 0 (Upstroke) 1 2 (Plateau) 3 4 Peak Normal 0 Late I Na Peak Abnormal Q S T Q S T Twitch Phasic Phasic Tonic EAD DAD

23. Late I Na is involved in the Long QTS * Andersen—Tawil Syndrome ** Timothy Syndrome 1505-1507  Late I Na SNTA1,  -1 Syntrophin LQT12  I Ks AKAP9, Yotiao LQT11  Late I Na SCN4B, NavB4 LQT10  Late I Na CAV3, Caveolin-3 LQT9  I Ca CACNA1C, Ca v 1.2 LQT8**  I K1 KCNJ2, Kir2.1 LQT7*  I Kr KCN2, MiRP1 LQT6  I Ks KCNE1, minK LQT5  Ca i ,  Late I Na ? KCNH2, HERG LQT4  Late I Na KCNQ1, KvLQT1 LQT3  I Kr KCNH2, HERG LQT2  I Ks KCNQ1, KvLQT1 LQT1 Channel Gene 50 ms 5 pA Normal 50 ms Enhanced (  KPQ) I NaL I NaL

25. Ranolazine selectively inhibits the late I Na Late I Na Peak I Na abnormal Ranolazine Control Δ IC 50 = 38-fold A. Ventricular Myocytes from Canine Failing Hearts 50 0 100 % Inhibition Peak IC 50 = 244 µM late IC 50 = 6.5 µM 1E-3 0.01 0.1 1 10 100 Concentration of Ranolazine (mM) Rajamani S., et al., Eur Heart J 207;28: 400 (abstract) ACE que no se controla con otros antianginosos, o en pacientes que no pueden tomar estos medicamentos. O OH CH 3 CH 3 OCH 3 H N N N O

26. Ranolazine: mechanism of action Hasenfuss G, Maier LS. Clin Res Cardiol 2008;97:222-26 Maier LS. Cardiol Clin 2008;26:603-14. Ischemia ↑ Late I Na Na + overload Ca ++ overload Mechanical dysfunction ↑ Diastolic tension ↓ Contractility Electrical dysfunction Arrhythmias O2 supply & demand ↑ ATP consumption ↓ ATP formation NCX NCX: sodium-calcium exchanger Ranolazine

27. Ranolazine reduces Na + and Ca 2+ overload induced by ATX-II in rabbit myocytes Sossalla S et al. J Mol Cell Cardiol 2008; 45: 32-43. 0 10 20 30 * End-diastolic pressure (mmHg) 40 * P<0.05 Control Ranolazine Na + overload Diastolic [Ca 2+ ] i

28. Ranolazine reduces the increase in diastolic tension in LV trabeculae from human failing heart Sossalla S et al.. J Mol Cell Cardiol 2008; 45: 32-43.

29. Ranolazine: Key Clinical Trials ROLE N=746 Chronic angina Chaitman BR, et al. JAMA. 2004;291:309-316. Stone PH, et al. J Am Coll Cardiol. 2006;48:566-575. Morrow DA, et al. JAMA. 2007;297:1775-1783. J Am Coll Cardiol 2004;43:1375– 82 CARISA N=823 Chronic angina Ranolazine vs placebo on top of standard therapy ERICA N=565 Chronic angina Ranolazine vs placebo on top of amlodipine 10mg MERLIN TIMI-36 N=6560 Non-STE ACS Ranolazine vs placebo on top of standard care MARISA N=191 Chronic angina Ranolazine vs placebo Total patients enrolled = 8,139

30. CARISA Efficacy Change from baseline (sec) Peak Trough *** ** ** *** ** * * * * * 50 100 150 Exercise duration Time to angina Time to 1-mm ST-depression Exercise duration Time to angina Time to 1-mm ST-depression Placebo Ranolazine 750 mg b.i.d. Ranolazine 1,000 mg b.i.d. n = 791, ITT/LOCF; LS means ± SE. *p<0.05; **p  0.01 ***p  0.001 vs placebo ITT: Intent To Treat LOCF: Last Observation Carried Forward Chaitman BR, et al. JAMA 2004;291:309-16.

31. MERLIN TIMI-36 trial CV Death, MI, or Recurrent Ischaemia (% at 12 months) 0 10 20 30 0 180 360 540 Days from randomisation HR 0.92 (95% CI 0.83 to 1.02) P=0.11 Ranolazine 21.8% (n=3,279) Placebo 23.5% (n=3,281) Recurrent Ischemia (%) Days from Randomization Ranolazine 17.3% (N=3,279) Placebo 20.0% (N=3,281) HR 0.87 (95% CI 0.76 to 0.99) P =0.030 0.00 0.05 0.10 0.15 0.20 0.25 0 180 360 540 Percentage (%) p=0.048 p=0.005 p=0.002 8.1 16.4 21.1 5.6 12.5 16.5 0 5 10 15 20 25 Worsening Angina New anti- anginal therapy Reccurrent Ischemia Placebo n = 1,776) Ranolazine n = 1,789)

32. Rate of tachyarrhythmias detected on cECG monitoring after Non-ST-segment MI Scirica et al. Circulation 2007;116:1647-1652.

33. Scirica et al. Circulation 2007 Morrow, D. A. et al. Circulation 2009 Cahnege in HbA1c and estimated risk of recurrent ischemia at 1 year in patients allocated to ranolazine vs placebo stratified by diabetes status 0.48% reduction (P = 0.008 Ranolazine 750 mg bid vs placebo

34. Short-term safety and tolerability 8 (2.8) 7 (2.5) 2 (1.1) 1 (0.6) 4 (2.2) 6 (2.2) 7 (2.5) 4 (1.5) Headache N/A N/A 2 (1.1) 0 4 (2.2) 6 (2.2) 4 (1.4) 5 (1.9) Fatigue 6 (2.1) 3 (1.1) 1 (0.6) 0 0 9 (3.3) 1 (0.4) 1 (0.4) Asthenia 8 (2.8) 2 (0.7) 2 (1.1) 1 (0.6) 1 (0.6) 15 (5.5) 10 (3.6) 2 (0.7) Nausea 11 (3.9) 7 (2.5) 8 (4.4) 2 (1.1) 1 (0.6) 19 (6.9) 10 (3.6) 5 (1.9) Dizziness 25 (8.9) 5 (1.8) 4 (2.2) 0 0 20 (7.3) 17 (6.1) 2 (0.7) Constipation 112 (39.9) 100 (35.3) 41 (22.8) 29 (16.0) 27 (15.1) 90 (32.7) 87 (31.2) 71 (26.4) Any AE Treatment-emergent adverse events (AE) reported in ≥2% of patients and more frequently on ranolazine than on placebo No modifica los intervales RR, PR, QRS or QTc* 1,000 mg n=281 Placebo n=283 1,000 mg n=180 500 mg n=181 Placebo n=179 1,000 mg n=275 750 mg n=279 Placebo n=269 ERICA Trial bid for 6 wks MARISA Trial bid dosing 1 week CARISA Trial bid for 12 weeks