Rome Cardiology Forum

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1 Rome Cardiology Forum Update on Atrial Fibrillation Rome, January 29 th -31 st 214 Pharmacological Prevention of Atrial Fibrillation John Camm St. George s University of London, UK Conflicts of Interest: Consultant/Advisor/Speaker Advisor / Speaker : Astra Zeneca, ChanRX, Gilead, Merck, Menarini, Otsuka, Sanofi, Servier, Xention, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, Pfizer, Boston Scientific, Biotronik, Medtronic, St. Jude Medical, Actelion, GlaxoSmithKline, InfoBionic, Incarda, Johnson and Johnson, Mitsubishi, Novartis, Takeda

2 History of Antiarrhythmic Drugs 1914 Quinidine 1962 Verapamil 1964 Propranolol 1965 Bretylium 1969 Diltiazem 195 Lidocaine 1951 Procainamide 1956 Ajmaline 1962 Disopyramide 1967 Amiodarone 1972 Mexiletine 1973 Aprindine, Tocainide 1975 Flecainide 1976 Propafenone 1985 Sotalol 2 Dofetilide Vernakalant AF Only

3 Antiarrhythmic Medical Therapies Class Ia: Disopyramide, Quinidine and Procainamide Class 1b: mexiletine, tocainide Amiodarone Sotalol Class III Beta blocker Antiarrhythmic Agents New and Old Class Ic Propafenone Flecainide Nexterone and Budiodarone Dofetilide USA only Abandoned Tedisamil Vanoxerine New Class III Agents Vernakalant ICD/VT Azimilide only Abandoned Celivarone Multichannel blockers Upstream therapies Modified from Savelieva I and Camm AJ. Europace 28:1: SAC Blockers Ranolazine Late Na blockers Na+/Ca2+ Inhibitor Novel Drugs Rotigaptide Connexin Dangaptide Modulator IKACh NTC-81 Blocker Chloroquine IK1 IKur Xen 13 Blockers Blockers Anti inflammatory Colchicine Ryanodine Receptor Modulator Na+/H+ Inhibitor

4 Free from AF recurrence (OT / ITT) Conversion to SR [%] SAFE-T Sotalol Amiodarone AF Efficacy Trial VA Cooperative Study N=665, 2% AF >1 year: Amio 267, Sot 261, Placebo 137 Follow-up 1year with TTM weekly 1 o EP: time to 1st AF recn after CV Sotalol Placebo Singh BN et al. NEJM. 25;352: Amiodarone Days Spontaneous DCC Failed CV Total Placebo Sotalol Amiodarone

5 AADs for Mortality Reduction after DCC Systematic Review of RCTs Overall Mortality Class IA Class IC Metoprolol Class III Amio Dofetilide Sotalol Q vs Class I Q vs Sotalol Amio vs Class I Amio vs Sotalol Sotalol vs Class I.4.9 Lafuente-Lafuente C, et al, Arch Intern Med 26;166: Odds Ratio (95% CI)

6 % Without event % Without event Rates of Mortality and Hospitalizations AFFIRM Study by Treatment Group Composite endpoint (ACM + CVH) CV hospitalization AFFIRM Age, yrs Rate n= 227 Amio N =735 Other AADs n= P =.23 P =.38 Rate control Amiodarone Other AADs 1 8 Rate control Amiodarone Other AADs Men, % CAD,% CMP,% CHF,% p < Years 2 p < Years Saksena S, et al. Abstracts, ACC 21

7 and Amiodarone Main Ion Channel/Receptor Effects Outward currents Amiodarone I Kr (ventricle) Guinea pig (IC 5 ; µm) I Ks (ventricle) Guinea pig (IC 5 ; µm) 1 3 I K1 (ventricle) Guinea pig (IC 5 ; µm) >3 <3 I K(Ach) (atrium) Guinea pig (IC 5 ; µm).1 1 Inward currents Amiodarone I Na (human; 3 µm) 97% block 41% block I Ca(L) (Guinea pig; 1 µm) 76% block 85% block Beta blockade (IC 5 ; µm)

8 Cumulative Incidence (%) ATHENA: Primary Outcome Time to first cardiovascular hospitalization or death 5 4 HR =.76 P < Placebo Mean follow-up 21 5 months Months Patients at risk Placebo Hohnloser SH et al. ATHENA Investigators. N Engl J Med. 29 Feb 12;36(7):

9 as an Antiarrhythmic Examples from ATHENA Time to 1 st DCV Cumulative incidence, % Time to 1 st AF/AFL Cumulative incidence of AF/AFL, % No. in Permanent AF Number of Patients HR =.69 p <.1 Placebo Months HR =.75 p <.1 Placebo Months (12.7%) n= 2313 p< (7.7%) n= 2291 Placebo on top of standard Rx Page R, et al. Am J Cardiol 211 All AF related hospitalization: HR=.626, 95% CI = [.54;.73] First AF related hospitalization: HR=.63, 95% CI = [.55;.72]

10 Cumulative Incidence (%) Was Antiarrhythmic Effect Important? Permanent AF Patients 5 Cardiovascular Hospitalization or Death HR=.74 p=.96 Placebo Months Placebo Mean follow-up 21 ± 5 months - on Study

11 PALLAS Permanent Atrial fibrillation outcome Study DRONEDARONE Screen Permanent AF 6m + CV risk No NYHA unstable III or IV NYHA CHF R 2 years, recruitment; 12 m min FU common end-date 1,8 patients; 844 events 9% power for 2% RRR and 2 sided alpha of 5% PLACEBO 1 Outcomes 1 st Co-primary (Stroke/MI/SEE/CV Death) 2 nd Co-primary (All Death/Unplanned CV Hospitalization) (n = 1619) Placebo (n = 1617) vs Placebo Events %/yr Events %/yr HR 95% CI P value <.1 Connolly S. et al. N Engl J Med. 211 Nov 14. [Epub ahead of print]

12 ATHENA (Overall) vs PALLAS Risk Factors PALLAS Risk Factors ATHENA (Overall) n = 231 % Placebo n = 2327 % (n = 1619) % PALLAS Placebo (n = 1617) % CAD Prior Stroke/TIA Symptomatic HF LVEF < 4% Peripheral Arterial Disease Age > 75 with HTN & Diabetes Hohnloser SH, et al. N Engl J Med. 29;36: Connolly S. et al. N Engl J Med 211 Dec 15;365(24):

13 Sub-groups 2 nd Co-Primary Outcome Characteristics N HR [95% CI] a Hazard Ration (95% CI) P value b Overall 1.95 [1.45;2.62] Age < [1.42;3.52] [1.19;2.59] Duration of perm. AF 6 months to 2 years [1.2;3.4] >2 years [1.32;2.85] Baseline LVEF LVEF 4% [1.15;4.7] LVEF>4% [1.35;2.64] NYHA No class II/III [1.23;3.36] Class II/III [1.32;2.75] CHADS CHADS [1.16;3.19] CHADS > [1.36;2.82] Stroke or TIA history N [1.49;3.1] Y [.88;2.72] Coronary artery disease N [1.23;2.84] Y [1.3;3.1] Baseline HR HR <65 bpm [1.75;7.59] HR 65 bpm [1.2;2.32] Baseline SBP SBP <13 mmhg [1.19;2.83] SBP 13 mmhg [1.3;2.98] Digoxin N [1.44;2.97] Y [1.2;2.83] Beta blocking agents N [.97;2.71] Y [1.48;3.7] Vitamin K antagonist or Dabigatran N [.71;2.42] Y [1.59;3.14] Regions North America/Western Europe [1.48;3.51] Other regions [1.11;2.51] a: Determined from Cox regression model b: P-value of interaction between baseline characteristics and treatment based on cox regression model Connolly S. et al. N Engl J Med 211;365: LVEF NYHA HR Better Placebo Better

14 Post-market Experience: Magdeburg and Leipzig Registries Registry Magdeburg (MADRE) Leipzig # patients Age, yrs 63 ± 1 67 ± 9 PAF, % Duration, yrs 3.6 ± ± 6.8 HTN, % CAD, % Prior AAD, % Prior PVI Event rate, % MADRE 5 42 Recurrence Stopped For inefficacy MADRE Leipzig For side effects Leipzig Follow-up, mos 14.3 ± More effective in non-lone AF (62% vs 84%), U-shape relationship with LA size Said SM, et al. Int J Cardiol 213;167:26-4 Said SM, et al. JCP 213;53: Adverse events 7.3 GI disorders Bradycardia QT prolongation Abnormal LFT 2.5

15 in PAF: HESTIA A placebo-controlled, double-blind, randomized, multi-center study to assess the effects of 4 mg BID for 12 weeks on atrial fibrillation (AF) burden in subjects with permanent pacemakers The virgin goddess of the hearth and the home 2 1 o EP: changes in AF burden from baseline at 12 weeks, % Placebo 12,8 Placeboextracted change Patients with PAF and DDD PM Planned n = 29, Enrolled n = 112 AF burden at baseline Placebo vs : 16% vs 21% Duration: 4 weeks baseline, 12 weeks therapy At 12 weeks: 23 vs 18% -54,4-59, to % p=.15

16 Department of Defence Database Overview Overall Results N=279 Other AADs N=4158 Digoxin N=4158 Number of event Percentages p-value(1) Death from Any Cause Propensity-score matching of 279 patients on dronedarone and 4158 patients on other AADs, and 4158 on digoxin.34% Ref.73%.79.87% Kaplan-Meier Curves % Remaining event free Other AADs Digoxin Event-Rate / 1, PM p- value 5.16 Ref HR (95%CI) P-value Ref 2.28 (1. 5.2) ( ).19 All-cause mortality was significantly higher in the other AADs (p=.49) and digoxin (p=.19) Goehring E, et al. 213 ACC San Francisco Months after index date Hazard ratio [HR] (Other AADs vs = 2.28; CI:1. to 5.2; P <.5])

17 % Inhibition Number of patients Ranolazine New-Onset Atrial Fibrillation Sodium Current 1 =2, RR.74, p=.8 75 (2.3%) Late I Na 5 55 (1.7%) Peak I Na 1. Human Cardiac NaCh in HEK293 Cells Peak IC 5 = 428 µm Placebo Ranolazine.5 Late IC 5 = 6.9 µm. 1E Concentration of Ranolazine (mm) Rajamani S., et al., Eur Heart J. 28(1) 27 Scirica et al. Circulation. 27;116:

18 Ranolazine versus Amiodarone AF Prophylaxis After CABG Retrospective cohort study 393 pts undergoing CABG Amiodarone (4 mg preoperative followed by 2 mg twice daily for 1 14 days) - N=211 (53.7%) Ranolazine (1,5 mg preoperative followed by 1, mg twice daily for 1 14 days) - N=182 (46.3%) Mean age 65 ± 1 years, 72% male P =.35 Not approved CABG=coronary artery bypass grafting Murdock D, et al. ACC Abstracts 211, New Orleans, LA, USA Ranolazine associated independently with a reduction of post-op AF

19 V max (% of control at 5 ms CL) Induction or termination of persistent AF, % Synergistic Effect on AF of Combination of Ranolazine and Canine isolated coronaryperfused RA, LA, PV, and LV preparations Ranolazine 5 mol/l 1 mol/l Pulmonary vein preparations /1 ACh 83 5/6 ACh+ 71 5/ /6 1/5 ACh+Ranolazine AF induction AF termination 1 1/1 ACh+R+D 6 6/ * * * p <.5 vs control p <.5 vs R or D alone Control Ranolazine R+D * Burashnikov A, et al. J Am Coll Cardiol 21;56:

20 Proportion of patients converted to SR, % Pharmacological Cardioversion of AF Combination of Amiodarone and Ranolazine Not approved Pilot RCT N = 51 with AF < 48 h Age 63 8 years, 65% men HTN 68 77%, CAD 2 27% I.V. amio 5 mg/kg for 1 h followed by infusion of 5 mg/h for 24 h I.V. amio + ranolazine 1,5 mg p.o. 1 o EP: conversion within 24 h SR=sinus rhythm Fragakis N, et al. Am J Cardiol 212;11: Amio + Rano Amio Hours 22/25 (88%) p =.2 17/26 (65%) HR =.81 ( ) Median time to conversion: 18 h (Amio) vs 1 h (Amio+Rano)

21 Percent converted to NSR Vanoxerine and Pharmacologic AF CV The COR-ART Study 1% 9% 8% Percent Conversion to NSR 4 mg 3 mg 2 mg Placebo.838 Vanoxerine: potent blocker of IKr (herg) channel and Na and L- type Ca channel blocker Extensive safety experience as anti Parkinson Syndrome drug 7% 6%.18 Subjects who have been in symptomatic AF/AFL for 3 hours to <7 days 5% 4% <.1 Randomized, Double-Blind, Placebo-Controlled, Dose-Modifying 3% 2% Overall p =.5 1% % Time (hours) Dittrich H, et al. AHA Poster Dallas 213 Placebo - 3 patients 2 mg - 25 patients 3 mg - 25 patients 4 mg - 25 patients No VT adverse event 1 sinus pause (3s) at 2 mg 3 QT prolongation at 4 mg

22 Conclusions Amiodarone is the best AAD drug to suppress recurrences of AF, but does not reduce mortality or hospitalisation reduces CV hospitalisations and? CV mortality in patients with recurrent forms of AF should not be used in patients with permanent AF, or moderate or severe heart failure/lv dysfunction There have been promising reports on the antiarrhythmic potential of ranolazine, but definitive studies are awaited The development of many potential antiarrhythmic agents has been suspended others continue to be developed

23 Thank you for your attention

24 When Use Atrial Fibrillation No Heart Failure Heart Failure Recurrent Permanent Paroxysmal Persistent SR Camm J, et al. Heart 213;99: Cardioversion No

25 RAFFAELLO: Ranolazine in Atrial Fibrillation Following An ELectricaL cardioversion Phase IIb ~ 4 centres in Europe (Germany, Italy, Spain, UK) Planned DCC off AADs; SR maintained for 2 h Ranolazine: 375, 5, 75 mg bd or Placebo Treatment duration: 16 weeks or until documented AF recurrence in need of medical intervention Recruitment completed (n = 26), database locked

26 Clinical Trial RANO+DRONE Combination: HARMONY PAF with pacemakers N = 15, 45 centres Follow-up: 12 weeks Primary endpoint: reduction in AF burden Secondary endpoints: AF burden at each clinic visit at 4, 8, 12 weeks and the number of AF episodes Expected March 214 Placebo + Placebo + Placebo Ranolazine + Placebo Ranolazine + dose 1 NCT Ranolazine + dose 2