L’azione antiaritmica – The Anti-Arrhythmic Action 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

IKr – rapidly activating component of delayed rectifier current Late INa – late sodium current INa late normalized current Tail Current (Normalized) 2 6 2 6 Ranolazine Concentration (mM/L) Late ICa – late calcium current Canine ventricular myocytes Ranolazine Concentration 2-6 mM/L: therapeutic range Normalized current 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

Ranolazine Concentration (mM/L) Effects of ranolazine on epicardial and M cell Action Potential Duration – APD50/90: 50/90% repolarization M cell (N=5) M cell (N=5) Epicardial cell (N=4) Epicardial cell (N=5) APD50 (ms) APD90 (ms) 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

Progressive reduction of waveforms Rapid pacing DC Shock 2-4 different waveforms Persisting VF Rapid pacing VF + Ranolazine 10mM VF interruption (12+6 s) Progressive reduction of waveforms Isolated Rat Hearts (N=8) Morita N, 2011

Multifocal activation VF Pseudo-ECG Ranolazine 10mM VF interruption 1.1+0.4 m Micro-Electrode EADs H2O2 (0.1 mM) H2O2 (0.1 mM) EADs Ranolazine stop VF 36+10 min Multifocal activation VF Isolated Rat Hearts (N=8) Morita N, 2011

Time course of the reduction in the number of foci after ranolazine perfusion. H2O2 (0.1 mM) Ranolazine 10mM Number of Foci per 100 ms VF termination (SR) 1 second VF SR Morita N, 2011

Termination of PACs (%) Termination of PACs (%) Sossalla S, 2010 Incidence of PACs (%) Ca2+-induced PACs Termination of PACs (%) Incidence of PACs (%) Termination of PACs (%) Iso-induced PACs Vehicle Ranolazine Vehicle Ranolazine

Late INa integral (ms•A/F) Sossalla S, 2010 Baseline Sinus rhythm Atrial Fibrillation Frequency (Hz) Frequency (Hz) Frequency (Hz) Peak INa (A/F) Late INa integral (ms•A/F) *: 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 Right ventricle Vehicle N=6 - closed-chest anesthetized pigs Ranolazine +57 Ranolazine Effective refractory period (ms) Right Atrium N=7 - closed-chest anesthetized pigs Vehicle Time (min) Carvas M, J Cardiovasc Pharmacol 2010 *: P<0.05 vs Baseline

Intensity (mA) Intensity (mA) Time (min) Ranolazine 50 mg (2mL) - Intra-pericardial injection Intensity (mA) Right ventricle 24 29 Ventricular Fibrillation Threshold *: P<0.05 vs Baseline Intensity (mA) Time (min) Right Atrium 5 29 Atrial Fibrillation Threshold N=6 - closed-chest anesthetized pigs Carvas M, J Cardiovasc Pharmacol 2010

Atria Ventricle ERP ERP APD75 APD90 *: P<0.01 vs APD75 Control Rano (5mM) Chronic Amio Chronic Amio & Rano Control Rano (5mM) Chronic Amio Amio & Rano ERP: effective refractory period APD75/90: action potential duration at 75/90% of repolarizaion PRR: post-repolarization refractoriness Sicouri S, Circ Arrhythm Electrophysiol 2010

Right Atrial preparations *: P<0.05 vs Control & Ranolazine *: P<0.001 vs Control; †: P<0.01 vs Amiodarone & Ranolazine Control Rano (5mM) Chronic Amio Chronic Amio & Rano Control Rano (5mM) Chronic Amio Chronic Amio & Rano Vmax: maximum rate of rise of action potential upstroke DTE: diastolic threshold of excitation Sicouri S, Circ Arrhythm Electrophysiol 2010

The shortest CL with 1:1 activation (ms) Burashnikov A, 2010 Atria *: P<0.05 vs Control #: P<0.05 vs ERP ERP APD70 ERP and APD70 (ms) Vmax (% of Control) Atria *: P<0.05 vs Control Ventricle C Rano (5mM) WO Dron (10mM) Dron & Ran Atria Canine preparations Ventricle Pulmonary veins Pulmonary veins The shortest CL with 1:1 activation (ms) (% of Control at 5000 ms CL) Vmax *: P<0.05 vs Control *: P<0.05 vs Control C Rano (5mM) WO Dron (10mM) Dron & Ran C Rano (5mM) Dron (10mM) Dron & Ran

Induction of persistent AF (%) Termination of persistent AF (%) Burashnikov A, 2010 Effects of Ranolazine, Dronedarone, and Their Combination on ACh-Mediated Persistent AF in the Isolated Canine Coronary-Perfused Right Atria N=10 N=7 N=6 N=10 N=10 N=5 N=6 N=10 Induction of persistent AF (%) Termination of persistent AF (%) ACh (1 mM/L) Rano (5 mM/L) Dron (10 mM/L) Dron & Ran ACh (1 mM/L) Rano (5 mM/L) Dron (10 mM/L) Dron & Ran

Ventricular arrhythmias 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 P<0.05 Incidence (%) Duration (s) Sotalol Lido Rano Control Sotalol Lido Rano Control Lido: Lidocaine Rano: Ranolazine Dogs (N=20 per group) - 5’ proximal LAD occlusion; 5’ reperfusion Kloner RA, J Cardiovasc Pharmacol Ther 2010

Supraventricular Arrhythmias Ventricular Tachycardia Scirica BM, 2007 Ranolazine N=3162 - Age: 63 years Placebo N=3189 - Age: 63 years Supraventricular Arrhythmias p=0.08 AF SVT >3 b >4 b >8 b Ventricular Tachycardia P<0.001 Continuous ECG monitoring duration: 6.8 days P<0.001 Incidence (%) P=0.01 Bradycardia <45 bpm Pause >3 s

Hours from randomization Incidence of VT >8 beats Continuous ECG monitoring duration: 6.8 days RR=0.63 p<0.001 Placebo – 8.3% N=3189 - Age: 63 years RR=0.65 p<0.001 Ranolazine – 5.3% N=3162 - Age: 63 years RR=0.67 p=0.008 4.7% Incidence (%) 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=NS Amiodarone – 200 mg bid age: 65 years; LVEF: 55%; n=211 P=NS Ranolazine – 1000 mg bid age: 67 years; LVEF: 58%; n=182 Hospital admission 30 day Mortality 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

OR Effetti collaterali – Abbandono dello studio entro 12 mesi NNH: number needed to harm §: solo eventi pro-aritmici OR Effetti collaterali – Abbandono dello studio entro 12 mesi NNH Chinidina NS 9 42.9 Flecainide P=0.005 17§ Propafenone P=0.02 27 Classe IC P=0.002 13.7 Amiodarone P<0.001 27 Sotalolo NS 27 Classe III P<0.001 Amiodarone vs. Classe I P=0.004 Amiodarone vs. Sotalolo NS Lafuente-Lafuente C, Arch Int Med 2006 1 2 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

Late INa was significantly greater as well as Nav1.1 expression 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 pro-arrhythmogenic 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

Both agents have rapid unbinding kinetics from the Na+ channel 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 a- and 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