Targeting the late sodium channel: A new antiarrhythmic paradigm? Wojciech Zareba, MD, PhD Professor of Medicine/Cardiology University of Rochester Medical Center Rochester, NY Disclosures: - Gilead Sciences: research grants - Boston Scientific: research grants - Zoll: research grants
Late Sodium Current Saad et al. Clin Cardiol 2015
Ion Channel Currents: Effects of Ranolazine (Potencies) Inward currents I Na I Ca,L Peak I Na Late I Na Peak I Ca,L IC 50, mm 100* 5 296 Late I Ca,L 50 I Na-Ca 91 Outward currents I Kr I Ks I Kl I To IC 50, mm 12 <20% at 30 mm No effect No effect Canine LV myocytes; *Based on Vmax of AP; Adapted from Belardinelli et al. Eur Heart J Suppl. 2006.
Cellular Changes in Ischemia and Heart Failure Ischemia, Cardiomyopathy, Heart Failure O 2 Supply O 2 Demand Late I Na Na + Overload Ranolazine Inhibits Late I Na Ca ++ Overload Electrical Instability (VT/VF) Impaired Diastolic Relaxation Ju YK, et al. J Physiol. 1996. Murphy E, et al. Circ Res. 1991. Jansen MA, et al. Circulation. 2004. Min JY, et al. J Pharmacol Exp Ther. 1999. Fraser H, et al. J Mol Cell Cardiol. 2006. Crossman DC. Heart. 2004. Meyer M, et al. J Mol Cell Cardiol. 1998.
Time (seconds) CARISA: Ranolazine Increases Exercise Treadmill Test Performance Comparison to Placebo at Week 12 160 120 Primary endpoint 24.1s* 115.8 26.0s* 114.3 140.3 21.1s 125.1 146.2 26.1s* 37.9s* 126.8 Placebo + background therapy 1000 mg b.i.d. ranolazine + background therapy *P 0.05 34.6s* 80 91.7 91.5 88.9 93.8 40 65.4 59.2 0 Exercise duration Angina onset 1 mm ST depression Exercise duration Angina onset 1 mm ST depression Trough Peak The improvement in exercise treadmill tests in females was about 33% of that in males receiving 1000 mg b.i.d. ranolazine Tolerance to ranolazine did not develop after 12 weeks of therapy, and rebound angina, as measured by exercise duration, has not been observed Chaitman BR, et al. JAMA. 2004. Ranexa (ranolazine extended-release tablets) PI. February 2006. CVT data on file RAN00253-2.
ERICA: Ranolazine Reduces Angina Frequency and Nitroglycerin Use Comparison to Placebo at Week 6 Mean Number of Angina Attacks/Week Primary Endpoint Placebo + 10 mg amlodipine 1000 mg b.i.d. ranolazine + 10 mg amlodipine Mean Nitroglycerin Doses/Week 5 5 4 4.3 3.3* 23%; *P=0.028 4 3.6 25%; *P=0.014 3 3 2.7* 2 2 1 1 0 Double-blind 0 Double-blind The mean reduction in weekly angina attacks was 0.3 for females and 1.3 for males. Chaitman BR, et al. JAMA. 2004. Ranexa (ranolazine extended-release tablets) PI. February 2006. CVT data on file RAN00253-2.
MERLIN: Primary Endpoint 30 CV Death, MI, or Recurrent Ischemia (%) (% at 12 months) Placebo 23.5% (N=3,281) 20 10 0 HR 0.92 (95% CI 0.83 to 1.02) P = 0.11 0 180 360 540 Days from Randomization Ranolazine 21.8% (N=3,279) Morrow D, et al. JAMA. 2007;297:1775-83
Cumulative Probability of Primary Endpoint by BNP Levels and Effect of Ranolazine Morrow et al. JACC 2010;55:1189-96
Lancet, October 13, 2015
Evidence for Anti-arrhythmic properties of Ranolazine Pre-clinical & Clinical Atrial Ventricular
Clinical Evidence: Gain-of-Function Sodium Channelopathies Associated with AF 1. A Novel SCN5A Gain-of-Function Mutation MT1857 Associated with Familial Atrial Fibrillation Makiyama T. et al. JACC 2008;25:1326-34. depol. shift (16.4 mv) in V ½ of the Volt.-dep SSI ( atrial excitability and familial AF) 2. A mutation in the sodium channel is responsible for the association of long QT-syndrome and familial atrial fibrillation Benito B. et al. HR 2008;5:1434-1440. Y1795C mutation is associated w/large late I Na Combined phenotype of AF and LQT3. Sensitive to Flecainide 3. Gain-of-function mutation of Nav1.5 in atrial fibrillation enhances cellular excitability and lowers the threshold for action potential firing Qiugu Li et al. BBRC 2009; 380:132-137 K1493R mutation in the DIII-IV linker in close proximity to the fast inactivation IMF motif Depol. shift (5.13mV) in V ½ of the Volt. dep. SSI Decrease threshold for AP (25% less current); spontaneous APs
Late Sodium Current in Atrium Saad et al. Clin Cardiol 2015
EADs in Atria from SCN5A ΔKPQ Mice: Suppression by Ranolazine Lemoine et al. Cardiovascular Research 2011
Supraventricular Tachyarrhythmias Detected in 7-day Holter in the MERLIN - TIMI 36 Trial A. Supraventricular Tachycardia B. New-Onset Atrial Fibrillation =339, RR 0.81, p<0.001 =20, RR 0.74, p=0.08 2000 100 Number of patients 1500 1000 1752 (53.5%) 1413 (43.2%) Number of patients 50 75 (2.3%) 55 (1.7%) 0 Placebo Ranolazine 0 Placebo Ranolazine Scirica et al. Circulation. 116:1449-1457, 2007
Ranolazine Reduces the Risk for Symptomatic AF MERLIN TIMI 36 Trial Scirica et al. Europace 2015;17:32-7
Comparison of effectiveness and safety of ranolazine versus amiodarone for preventing atrial fibrillation after coronary artery bypass grafting. The patients received either amiodarone (400 mg preoperatively followed by 200 mg twice daily for 10 to 14 days) or ranolazine (1,500 mg preoperatively followed by 1,000 mg twice daily for 10 to 14 days). The primary end point was any identified AF after CABG. A total of 393 consecutive patients undergoing CABG (mean age 65 ± 10 years, 72% men) received either amiodarone (n = 211 [53.7%]) or ranolazine (n = 182 [46.3%]). AF occurred in 26.5% of the amiodarone-treated patients compared to 17.5% of the ranolazine-treated patient (p = 0.035). Miles et al. Am J Cardiol 2011;108:673-6
Ranolazine enhances the efficacy of amiodarone for conversion of recent-onset atrial fibrillation 121 patients (64 ± 10 years) with recent-onset (<48 h duration) AF. 24 h amiodarone infusion (loading dose 5 mg/kg followed by maintenance dose of 50 mg/h; n = 60), or amiodarone infusion at the same dosage plus a single oral dose of ranolazine 1500 mg. Conversion rate at 24h Time to Conversion Amiodarone only 70 % 13.3+4.1h Amiodarone + Ranolazine 87 % 10.2+3.3h p value 0.024 0.001 Koskinas et al. Europace 2014;16:973-9
Ranolazine in Atrial Fibrillation Following An ELectricaL CardiOversion (RAFFAELLO) Dose-ranging Phase II study testing the efficacy and safety of 3 doses of Ranolazine (low, intermediate and high, given BID) versus placebo in maintaining sinus rhythm after successful electrical cardioversion in patients with persistent atrial fibrillation (AFib). Studied Patients: Persistent AF patients undergoing successful electrical cardioversion Endpoint: Maintenance of sinus rhythm up to 16 weeks ClinicalTrials.gov (NCT01534962)
Ranolazine in Atrial Fibrillation Following An ELectricaL CardiOversion (RAFFAELLO) De Ferrari et al. Heart Rhythm 2015;12:872 878
Ranolazine in Atrial Fibrillation Following An ELectricaL CardiOversion (RAFFAELLO) The incidence of AF recurrences were: - on placebo - 56.4% - on ranolazine 375-mg - 56.9% - on ranolazine 500-mg - 41.7% - on ranolazine 750-mg - 39.7%
Burashnikov et al. J Am Coll Cardiol 2010;56:1216 24
Heart Rhythm 2015;12:836 844
HARMONY Trial A Phase 2, Proof of Concept, Randomized, Placebo- Controlled, Parallel Study to Evaluate the Effect of Ranolazine and Dronedarone When Given Alone and in Combination on Atrial Fibrillation Burden in Subjects with Paroxysmal Atrial Fibrillation Studied Patients: Paroxysmal AF Dual chamber pacemaker with atrial arrhythmia algorithm detection Endpoint: AF Burden (AFB) ClinicalTrials.gov (NCT01522651)
HARMONY Trial Ranolazine (Ran): antianginal approved in 2005 Dronedarone (Dron): anti-af approved in 2009 Ran and Dron are multi-ion channel blockers In atrial myocytes Ran: peak and late I Na ( I Kr moderate) Dron: I Kr, I KACh, I f ( peak I Na ) Mechanism for synergism Inhibitions of peak I Na (Ran >> Dron) & I Kr (Dron >> Ran) Inhibition of late I Na stabilizes ventricular repolarization and suppresses triggered activity Safety: Plasma concentrations of Dron are ~2-fold lower than MULTAQ Inhibition of late I Na prevents VT (e.g. TdP)
HARMONY Trial Day 1 Randomization # (AFB 2 and 70%) Follow-up Run-in (4wks) * * * * Wks 1-4 Wks 5-8 Wks 9-12 Baseline Treatment Placebo Ranolazine 750 mg bid Dronedarone 225 mg bid Ranolazine 750 mg bid and dronedarone 225 mg bid Ranolazine 750 mg bid and dronedarone 150 mg bid # Stratified by AFB<15% and >15% * PPM Interrogation Results to Core EP lab (EGMs adjudicated)
Paroxysmal AF Inclusion Criteria Dual chamber pacemaker Atrial arrhythmia algorithm detection Implanted at least 3 months prior to the screening AF Burden (AFB)* 1% and 70% 2% and 70% Screening Randomization *AF burden: total time a subject is in AF expressed as a percentage of total recording time
Primary Endpoint: % Change from Baseline in AFB over 12 weeks PL D225 R750 R750/ D150 R750/ D225 Synergy (R750 +D225) R750/ D150 R750/ D225 p = 0.78 p = 0.49 p = 0.072 p = 0.008 Reiffel et al. Circ Arrhythm Electrophysiol 2015 Oct;8(5):1048-56
Number of Patients Patients with 70% Reduction from Baseline in AFB Over 12 Weeks 10 45% 8 6 27% 4 17% 2 11% 9% PL D225 R750 R750/ D150 R750/ D225 Reiffel et al. Circ Arrhythm Electrophysiol 2015 Oct;8(5):1048-56
Late Na+ current blockade in atria with ranolazine Late Na+ current place a significant role in atria Ranolazine suppresses diastolic depolarization, EAD and DAD in atria Concomitant IKr blockade seems to be important to achieve antiarrhythmic effect in atria Ranolazine seems to reduce recurrences of atrial fibrillation Combination of ranolazine (750 mg) and dronedarone (225 or 150 mg) reduces AF burden
Evidence for Anti-arrhythmic properties of Ranolazine Pre-clinical & Clinical Atrial Ventricular
Late Sodium Current in Ventricle Saad et al. Clin Cardiol 2015
Suppression and Termination of EAD-mediated Triggered Activity and VF by Ranolazine in Hearts Exposed to H 2 0 2 A. Baseline H 2 O 2 + Ran (1.2 min) ECG H 2 O 2 (8 min) H 2 O 2 + Ran (40 min) H 2 O 2 (10 min) H 2 O 2 + Ran Wash (40 min) H 2 O 2 (12 min) H 2 O 2 + Ran Wash (65 min) 1s Morita N, Karagueuzian H, et al. JACC 57:366-375, 2011
Risk of Sudden Cardiac Death Associated with Sudden Cardiac Death Ventricular Tachycardia Lasting 8 Beats 8% NO VT Patients with No VT 8 beats HR 0.96 (95% CI 0.66, 1.42); p=0.85 8% VT Patients with VT 8 beats HR 0.36 (95% CI 0.10, 1.27); p=0.097 Sudden Cardiac Death 6% 4% 2% Placebo 6% 4% 2% Placebo Ranolazine Ranolazine 0% 0 90 180 270 360 450 540 Days After Randomization Wang W et al. Circulation 120(18): S661, 2562, 2009 Modified from Scirica B et al, Circulation 122:455, 2010 0% 0 90 180 270 360 450 540 Days After Randomization Given the statistically neutral primary efficacy analysis of the MERLIN TIMI-36 trial, this analysis should be regarded as inherently exploratory.
RAID Trial Ranolazine in High Risk ICD Patients (NIH PI: W. Zareba) Significance: The only pharmacological phase III trial in the world testing new antiarrhythmic agent for ventricular arrhythmias Primary Aim: to determine whether ranolazine administration will decrease the time to first composite arrhythmia endpoint consisting of ventricular tachycardia or ventricular fibrillation (VT/VF) requiring ICD therapy (ATP or shocks) or death Study Population: 1,440 patients enrolled in >80 sites Expected Completion: 2016
RAID Trial Study Population Secondary Prevention Patients Subjects with ischemic or nonischemic cardiomyopathy after documented VT/VF or cardiac arrest. Primary Prevention ICD/CRT-D Patients with EF 35% who have experienced at least ONE episode of VT/VF appropriately treated with ICD or documented NSVT by ICD. implanted within the last 2 years with ONE of the following: BUN 26 mg/dl QRS>120ms Atrial Fibrillation >500/VPBs on Holter NSVT on Holter.