LA RANOLAZINA UN NUOVO FARMACO CON UN’AZIONE DI CLASSE / RANOLAZINE, A NEW DRUG WITH A CLASS ACTION L’azione antiaritmica – The Anti-Arrhythmic Action Stefano Fumagalli SOD Cardiologia e Medicina Geriatrica AOU Careggi e Università di Firenze 2 6 Late ICa – late calcium current Late INa – late sodium current INa late normalized current Tail Current (Normalized) IKr – rapidly activating component of delayed rectifier current 2 6 Ranolazine Concentration (mM/L) Normalized current Canine ventricular myocytes Ranolazine Concentration 2-6 mM/L: therapeutic range Inhibition of IKr by ranolazine prolongs APD, and its effect to inhibit late INa and late ICa,L abbreviates APD 2 6 Ranolazine Concentration (mM/L) Antzelevitch C, 2004 Effects of ranolazine on epicardial and M cell Action Potential Duration – APD50/90: 50/90% repolarization M cell (N=5) Epicardial cell (N=5) APD90 (ms) APD50 (ms) M cell (N=5) Epicardial cell (N=4) Control 1 5 10 50 100 Ranolazine Concentration (mM/L) Control 1 5 10 50 100 Ranolazine Concentration (mM/L) K+ Concentration: 4 mM/L *: P<0.05 vs Control Antzelevitch C, 2004 Rapid pacing DC Shock 2-4 different waveforms Persisting VF Rapid pacing VF + Ranolazine 10mM VF interruption (12+6 s) Isolated Rat Hearts (N=8) Progressive reduction of waveforms Morita N, 2011 VF Pseudo-ECG MicroElectrode EADs H2O2 VF (0.1 mM) interruption 1.1+0.4 m H2O2 Ranolazine 10mM (0.1 mM) EADs Ranolazine stop VF 36+10 min Multifocal activation Isolated Rat Hearts (N=8) VF Morita N, 2011 Number of Foci per 100 ms Time course of the reduction in the number of foci after ranolazine perfusion. H2O2 (0.1 mM) Ranolazine 10mM VF termination (SR) 1 second VF SR Morita N, 2011 Termination of PACs (%) Incidence of PACs (%) Incidence of PACs (%) Termination of PACs (%) Ca2+-induced PACs Iso-induced PACs Sossalla S, 2010 Vehicle Ranolazine Vehicle Ranolazine Sossalla S, 2010 Sinus rhythm Atrial Fibrillation Frequency (Hz) Frequency (Hz) Frequency (Hz) Late INa integral (ms•A/F) Peak INa (A/F) Baseline *: P<0.05 vs SR * / #: P<0.05 vs Vehicle / Baseline *: P<0.05 vs Vehicle Effective refractory period (ms) Ranolazine 50 mg (2mL) - Intra-pericardial injection Vehicle Right ventricle N=6 - closed-chest anesthetized pigs Ranolazine +57 Ranolazine Right Atrium N=7 - closed-chest anesthetized pigs Vehicle Time (min) *: P<0.05 vs Baseline Carvas M, J Cardiovasc Pharmacol 2010 Ranolazine 50 mg (2mL) - Intra-pericardial injection Intensity (mA) Intensity (mA) Right ventricle 29 Ventricular Fibrillation Threshold 24 *: P<0.05 vs Baseline 29 Right Atrium Atrial Fibrillation Threshold N=6 - closed-chest anesthetized pigs 5 Time (min) Carvas M, J Cardiovasc Pharmacol 2010 Atria Ventricle ERP ERP APD75 APD90 *: P<0.01 vs APD75 Control Rano (5mM) Chronic Chronic Amio Amio & Rano ERP: effective refractory period APD75/90: action potential duration at 75/90% of repolarizaion Control Rano (5mM) Chronic Chronic Amio Amio & Rano PRR: post-repolarization refractoriness Sicouri S, Circ Arrhythm Electrophysiol 2010 Right Atrial preparations *: P<0.05 vs Control *: P<0.001 vs Control; †: P<0.01 & Ranolazine vs Amiodarone & Ranolazine Control Rano Chronic Chronic (5mM) Amio Amio & Rano Control Rano Chronic Chronic (5mM) Amio Amio & Rano Vmax: maximum rate of rise of action potential upstroke DTE: diastolic threshold of excitation Sicouri S, Circ Arrhythm Electrophysiol 2010 Burashnikov A, 2010 *: P<0.05 vs Control Atria #: P<0.05 vs ERP Vmax (% of Control) ERP and APD70 (ms) ERP APD70 Atria Ventricle The shortest CL with 1:1 activation (ms) Atria Ventricle Pulmonary veins *: P<0.05 vs Control C Rano (5mM) WO Dron Dron (10mM) & Ran Vmax (% of Control at 5000 ms CL) C *: P<0.05 vs Control Rano WO Dron Dron (5mM) (10mM) & Ran Pulmonary veins Canine preparations *: P<0.05 vs Control C Rano Dron (5mM) (10mM) Dron & Ran Burashnikov A, 2010 Effects of Ranolazine, Dronedarone, and Their Combination on ACh-Mediated Persistent AF in the Isolated Canine Coronary-Perfused Right Atria N=7 N=6 ACh Rano Dron N=10 N=10 N=5 N=6 ACh Rano Dron N=10 Induction of persistent AF (%) Termination of persistent AF (%) N=10 (1 mM/L) (5 mM/L) (10 mM/L) Dron & Ran (1 mM/L) (5 mM/L) (10 mM/L) Dron & Ran First Direct Comparison of the Late Sodium Current Blocker Ranolazine to Established Antiarrhythmic Agents in an Ischemia/Reperfusion Model Ventricular arrhythmias VT episodes P=0.01 P<0.05 P<0.05 Duration (s) Incidence (%) P<0.05 Sotalol Lido: Lidocaine Rano: Ranolazine Lido Rano Control Dogs (N=20 per group) - 5’ proximal LAD occlusion; 5’ reperfusion Sotalol Lido Rano Control Kloner RA, J Cardiovasc Pharmacol Ther 2010 Scirica BM, 2007 Ranolazine Placebo N=3162 - Age: 63 years N=3189 - Age: 63 years P<0.001 Continuous ECG monitoring duration: 6.8 days P<0.001 Incidence (%) P<0.001 P<0.001 P<0.001 P=0.01 p=0.08 Bradycardia <45 bpm Pause >3 s AF SVT Supraventricular Arrhythmias >3 b >4 b >8 b Ventricular Tachycardia Incidence of VT >8 beats Continuous ECG monitoring duration: 6.8 days RR=0.63 p<0.001 Placebo – 8.3% Incidence (%) N=3189 - Age: 63 years RR=0.65 p<0.001 RR=0.67 p=0.008 Ranolazine – 5.3% N=3162 - Age: 63 years 4.7% 3.4% 3.1% P<0.001 2.3% Hours from randomization Scirica BM, 2007 Ranolazine versus Amiodarone for atrial fibrillation prophylaxis following coronary bypass surgery (%) P=0.035 P=NS Amiodarone – 200 mg bid age: 65 years; LVEF: 55%; n=211 P=NS Hospital 30 day admission Mortality Ranolazine – 1000 mg bid age: 67 years; LVEF: 58%; n=182 Atrial fibrillation Post-CABG events Murdock D et al, ACC, 60th Annual Scientific Sessions, 2011 Conclusioni La ranolazina sembra caratterizzata da un importante effetto antiaritmico … … dovuto non solo all’interazione con la corrente tardiva del sodio, ma al blocco di più canali cellulari Questo meccanismo d’azione rende la molecola molto vicina all’amiodarone in termini di efficacia Il miocardio atriale sembrerebbe più sensibile alle azioni della ranolazina, anche se alcuni dati pre-clinici e clinici sembrano confermare l’efficacia del farmaco anche nei confronti delle aritmie ventricolari L’utilizzo della ranolazina in associazione con amiodarone e dronedarone potrebbe portare ad una vera e propria sinergia clinica, permettendo la riduzione delle dosi degli anti-aritmici e diminuendo l’incidenza di eventi avversi NNH: number needed to harm §: solo eventi pro-aritmici OR Effetti collaterali – NNH Abbandono dello studio entro 12 mesi Chinidina NS 42.9 Flecainide Propafenone Classe IC P=0.005 17§ P=0.02 27 P=0.002 13.7 Amiodarone Sotalolo Classe III Amiodarone vs. Classe I Amiodarone vs. Sotalolo Lafuente-Lafuente C, Arch Int Med 2006 9 0 1 2 P<0.001 27 NS 27 P<0.001 P=0.004 NS 4 6 8 10 The major conclusion of this study is that the late Na current blocking drug ranolazine demonstrates efficacy against both pacing-induced re-entrant VF and spontaneous oxidative multifocal VF The suppression of multifocal VF is associated with a progressive reduction in the number of foci This finding supports the hypothesis that multifocal VF requires the constant generation of new interacting foci to maintain themselves such that when the rate of production of new foci falls below a critical level, VF terminates This is analogous to re-entrant VF, in which a critical mass is required to ensure that the rate of formation of new wavelets exceeds the rate of wavelet extinction Although H2O2 is an artificial means of inducing oxidative stress, there are many known triggers … stress in the heart, such as aging, heart failure, and ischemia–reperfusion, … all conditions associated with increased risk of VF Morita N, 2011 Sossalla S, 2010 The results show that permanent AF is associated with altered expression and function of Na+ channels Late INa was significantly greater as well as Nav1.1 expression Ranolazine reduced peak and late INa in SR, but it preferentially blocked late over peak INa in AF Ranolazine restores the physiological relationship between peak and late INa and consequently suppresses known proarrhythmogenic mechanisms in vitro Ranolazine reduced Ca2+- and Iso-induced PACs and caused a concentration-dependent and reversible negative inotropic effect associated with an improved diastolic tension Amiodarone action includes inhibition of a number of cardiac ionic currents (IKr, IKs, INa, late INa, Ito, ICa-L, ICa-T, IK1, IK(ACh), IK(ATP)) as well as aand b-adrenoceptor– blocking activity Ranolazine has been shown to have a pharmacological profile similar to that of chronic amiodarone … (and) causes inhibition of INa, IKr, and ICa Both agents have rapid unbinding kinetics from the Na+ channel Unlike amiodarone, which is an inactivated-state blocker of cardiac Na+ channels, ranolazine is an activated-state blocker The actions of amiodarone & ranolazine to produce potent block of the Na+ channels in the atria are similar to that of class IC antiarrhythmic agents. However, the effects of the combination are largely restricted to the atrial myocardium The potentiation by ranolazine of the anti-AF effects amiodarone may permit the use of a lower dose of amiodarone Sicouri S, Circ Arrhythm Electrophysiol 2010