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Mattias F. Duytschaever, MD, PhD Electrophysiology Unit AZ St.Jan-Brugge University Hospital Ghent Pharmacological Prevention of Atrial Fibrillation.

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Presentation on theme: "Mattias F. Duytschaever, MD, PhD Electrophysiology Unit AZ St.Jan-Brugge University Hospital Ghent Pharmacological Prevention of Atrial Fibrillation."— Presentation transcript:

1 Mattias F. Duytschaever, MD, PhD Electrophysiology Unit AZ St.Jan-Brugge University Hospital Ghent Pharmacological Prevention of Atrial Fibrillation

2 Bruxelles 2008

3  Atrial Fibrillation: The Clinical Problem − Changing Epidemiology of AF − Impact on Morbidity and Mortality  Pharmacological Prevention of AF − Conventional Anti-arrhythmic Drugs − New “Anti-arrhytmic drugs” for AF Outline of the Presentation Pharmacological Prevention of AF

4 Nieuwlaat et al, Eur Heart J 2005;26:2422 (Euro Heart Survey) Parameters Par AF (N=1571) Pers AF (N=1167) Age 64 ±1366 ±1271 ±11 Cardiomyopathy 7%13%16% Diabetes 15%16%22% Symptoms 77%73%55% Perm AF (N=1541) LAD (mm) 43 ±746±851±17 Valvular Heart Disease 19%24%40% Heart Failure 23%35%49% Clinically AF is a Multi-faceted Disease Atrial Fibrillation: The Clinical Problem

5 Age (yrs) Prevalence (%) Framingham Study Mayo Clinic Study CHS Rotterdam Study Prevalence (1 to 1.5%) and Incidence of AF Epidemiology of Atrial Fibrillation Age (yrs) Incidence/1000 person-years Miyasaka et al, Circ 2006;114: Framingham Study (men) CHS (men) Mayo Clinic (men) 9090 At 55y Life time risk for AF = 23.8% Heeringa et al, EHJ 2006;27: %

6 Estimated Prevalence Pool at 2050 Epidemiology of AF is Changing Go et al, JAMA 2001;285: Year Projected N of Pts with AF (millions) Miyasaka et al, Circulation 2006;114: Age-adjusted Incidence/1000 person-year % of AF>80y 2050:12 to 16 million Year 2050: 5.6 million

7 Wang et al., Circulation 2003;107:2920 Temporal Relations of AF and CHF and their Joint Influence on Mortality (The Framingham Heart Study) Incidence of AF 3-4% per year Atrial fibrillation Neurohormonal remodeling Atrial enlargement Atrial hypertrophy  atrial pressure Atrial stretch Atrial Fibrosis Electrical Remodeling Loss of atrial funct Non-physiologic HR Irregular V response Loss of AV synchronicity Another Vicious Circle Atrial Fibrillation and Heart Failure Underlying Heart Disease (AHT, LVH,VHD, age, diabetes,..) Heart Failure Cumulative Incidence of AF in Pts with CHF Years Epidemiology of AF is Changing

8 Outline of the Presentation  Atrial Fibrillation: The Clinical Problem − Changing Epidemiology of AF − Impact on Morbidity and Mortality  Pharmacological Prevention of AF − Conventional Anti-arrhythmic Drugs − New “Anti-arrhytmic drugs” for AF Pharmacological Prevention of AF

9 Impact of Atrial Fibrillation on Stroke  Yearly Risk of Stroke in Non- valvular AF is 5%  AF is Associated with a 2 to 7-fold Increased Risk for Stroke  The risk of Stroke increases Exponential with Age  20% of all Ischemic Strokes are Due to AF  40% of Patients with AF have Silent Brain Infarction  In Patients with AF there is Twice as much Cognitive Dysfunction or Dementia Miyasaka et al, European Heart J 2007;28: Age (yrs) Incidence of Dementia/1000 person-years General Men Men with AF Stroke Prevention in AF is a Pressing Health Concern

10 Jahangir et al, Circulation 2007;115: Survival Free of Death (%) Years observed expected % 68% 86% 57% Survival Free of Stroke/TIA (%) Years observed expected % 88% 96% 89% 72%* 85% Long-Term Outcome in Pts with Lone AF: a 30-year Follow-Up Study Impact of Atrial Fibrillation on Stroke

11 AF (men) Control (men) Total deaths 59.2*34.3 Deaths for CVS causes 49.9*21.2 Average time to death 5.9yr*7.7yr Mortality in AF Cases and Controls (Framingham Study) Impact of Atrial Fibrillation on Mortality Relative Risk of Mortality Whitehall Framingham Manitoba 2 4 Fuster et al, Circulation 2006;108:1979Kannel et al, NEJM 1982;306:1018

12 Middlekauff et al., Circulation,1991;84:40 Does Atrial Fibrillation Increase Mortality in Heart Failure? Impact of Atrial Fibrillation on Mortality Wellens et al., EHJ 2006;27:2740 Survival (%) FU (weeks) 20 AF at Baseline Sinus Rhythm P=0.0013

13 Neuberger et al, Eur H Journal, 2007;Sept 13 StudyN of AFEF(%)BB Impact of Atrial Fibrillation on Mortality Studies Adressing Mortality Risk of CHF Pts with AF at Baseline ACE/ARBRRP-value V-HeFT II (1993) 107/795 (FU 30m) 30%0%50% % vs 21% Mortality SOLVD (1998) 419/6517 (FU 33.4m) <35%20%50% % vs 23% Stevenson (1996) 140/750 (FU>24m) <40%0%60%1.12n.s.34% vs 25% COMET (2005) 600/3029 (FU 58m) <35%100%90% N.R. (higher) CHARM (2006) 670/7599 (FU 37.7m) <40%55% 1.38< /7599 (FU 37.7m) >40%55%20%1.80< % vs 28% 24% vs 14%

14 (1) New onset (Incident) AF is an Independent Risk Factor for Increased Mortality (“pre-terminal phenomenon”) Swedberg et al., Eur Heart J 2005;26:1303 (COMET) Wang et al., Circulation 2003;107:2920 (Framingham) (2) Prevalent AF is an Independent Risk Factor in Mild-to- moderate CHF Olsson et al., JACC 2006;47:1997 (CHARM) Crijns et al., Eur Heart J 2000;21:1238 (PRIME II) (3) Prevalent AF is an Independent Risk Factor in Ischemic Heart Failure Pedersen et al., Eur Heart J 2006;27:2866 (DIAMOND) Wellens et al., Eur Heart J 2006;27:2740 Impact of Atrial Fibrillation on Mortality Significance of AF in Heart Failure

15 Outline of the Presentation  Atrial Fibrillation: The Clinical Problem − Changing Epidemiology of AF − Impact on Morbidity and Mortality  Pharmacological Prevention of AF − Conventional Anti-arrhythmic Drugs − New “Anti-arrhytmic drugs” for AF Pharmacological Prevention of AF

16 Challenges of Therapies in AF Clinical Objectives for Therapy of AF  Prevention of Stroke  Preservation/improvement of LV Function  Relief of Symptoms  Reduction in Mortality The Preferred Strategy would be Pharmacological Rhythm Control, if Obtained Effectively and Safe

17 Importance of Sinus Rhythm!! Survival in CHF and AF (%) FU (months) 24 Placebo Amiodarone Rate Control Cumulative Mortality (%) n:352 n:306 Rhythm Control FU (months) Survival in CHF and AF (%) Sinus Rhythm Atrial Fibrillation Endpoint Free Survival (%) Sinus Rhythm Atrial Fibrillation FU (months) AFFIRM STAF CHF-STAT Rhythm vs RateSinus vs AF

18 Conventional Antiarrhythmic Drugs for AF Vaughan Williams Classification of Antiarrhythmic Agents Fuster et al., JACC 2001, page 1-70

19 CTAF, Roy et al., NEJM, Days of Follow-up Amiodarone Propafenone Sotalol SR (%) Duytschaever et al., PACE 1999 Duration>1year LVEDD LA <52 Digoxin Amiodarone Sotalol Age >75 Male Gender Absence of Recurrence 25% Predictors for RecurrenceMaintenance of Sinus Rhythm Efficacy of Class IC and III to Prevent Persistent AF Conventional Antiarrhythmic Drugs for AF

20 Lafuente-Lafuente C, et al, Arch Intern Med 2006;166: RCT included into analysis Total44 No. of patients 11,322 Placebo controlled 25 Active comparator 14 Persistent AF 38 (60% pts) PAF/recent onset 6 EF > 50% 41 Lone AF 1 Follow-up 1 year AF Recurrence Odds Ratio (95% CI) 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 Review of RCTs on Prevention of Recurrence of AF after DCC Conventional Antiarrhythmic Drugs for AF

21 Cumulative Mortality (%) Years (%) Rate Control Rhythm Control P=0.08 n:352 n:306 Primary Endpoint (Death) Rhythm Control v Rate Control (The AFFIRM Trial) Conventional Antiarrhythmic Drugs for AF Wyse et al. NEJM 2002  4060 patients, FU 5 year  Paroxysmal or Recurrent Persistent Asymptomatic AF  > 65 yr or Other RF for Stroke or Death  Rhythm Control : cardioversion, antiarrhythmic drugs, Stop coumadin if SR  Rate Control : heart rate from 80/’ en 110/’ ; continued coumadin

22 Conventional Antiarrhythmic Drugs for AF Primary Endpoint (Cardiovascular Death) Roy et al, NEJM 2008;358: Rhythm Control v Rate Control (The AF-CHF Trial)  1376 patients, FU >2 year  LVEF ≤ 35% and NYHA II-IV  AF ≥ 6 h within last 6 months or one episode ≥ 10 min within 6 months and prior D/C shock  82% amiodarone (rhythm control)

23 Flaker et al.(SPAF), JACC, 1992 Survival in Patients with CHF and AF (%) Follow-up (days) No Antiarrhythmic Drugs Antiarrhythmic Drugs (Quinidine, Procainamide, Disopyramide, Flecainide, Encainide) Survival in Patients with CHF and AF (%) Follow-up (months) 24 Placebo Amiodarone Singh et al.(CHF-STAT),Circulation, 1998 Conventional Antiarrhythmic Drugs for AF Class I and III Drugs are Not Safe (Certainly not in CHF)

24 Steinberg et al, Circulation 2004;109: CardiacVascular Non Cardiovascular Number of Deaths 5281 Cancer 2339 Pulmonary % of Sinus Rhythm 40% 60% EfficacySafety Class I and III Drugs are Not Effective Nor Safe Rate Rhythm 310 † 352 † Conventional Antiarrhythmic Drugs for AF

25 Fuster et al, Circulation 2006;108:1979 ACC/AHA/ESC 2006 guidelines for the management of AF Paroxysmal or Recurrent Persistent AF No Symptoms Antico and Rate Control Symptoms Antico and Rhythm Control Permanent AF Antico and Rate Control Conventional Antiarrhythmic Drugs for AF

26 Fuster et al, Circulation 2006;108:1979 No Heart Disease Amiodarone Catheter Ablation Flecainide Sotalol Coronary Artery Disease Amiodarone Catheter Ablation Heart Failure or Hypertension with LVH Catheter Ablation AmiodaroneSotalol ACC/AHA/ESC 2006 guidelines for the management of AF Conventional Antiarrhythmic Drugs for AF

27 Outline of the Presentation  Atrial Fibrillation: The Clinical Problem − Changing Epidemiology of AF − Impact on Morbidity and Mortality  Pharmacological Prevention of AF − Conventional Anti-arrhythmic Drugs − New “Anti-arrhytmic drugs” for AF Pharmacological Prevention of AF

28  Blocker Antiarrhythmic Agents New Class III Agents Novel Drugs TedisamilAzimilide Dronedarone Adenosine Agonist SAC Blockers ARDAs Na+/Ca2+ Inhibitor Na+/H+ Inhibitors Substrate therapies Amiodarone Sotalol Class III Quinidine Flecainide Class IC Multi-channel blockers Connexin modulators ARDAs (Vernakalant, AVE0118) Ranolazine “Antiarrhythmic” Drugs for AF Savelieva and Camm, Europace 2008;  Blocker ACEI ARB Statins PUFAs Pirfenidone Dofetilide Disopyramide Propafenone Class IA

29 Eloff et al., Circulation, dec 2003 Modulation of Gap Junctions 16 Weeks AF Inter Cellular Uncoupling Pharmacological Modulation of Atrial Conduction (Rotigaptide) Novel “Antiarrhythmic” Drugs for AF

30 Sinus Rhythm After 24 h of AF After 48 h of AF S1 S Control d-Sotalol Control d-Sotalol Control d-Sotalol ‘Early’ Class III AAD ms I Ca I Kur I Kr I Ks I to “Late” versus “ Early “ Class III Drugs Duytschaever et al., Cardiovascular Research, 2005,67:69-76 Late and Early Class III Drugs (Experimental) Novel “Antiarrhythmic” Drugs for AF

31 Savelieva and Camm, Europace 2008; Novel “Antiarrhythmic” Drugs for AF

32 Pacing Cycle Length (ms) Remodeled Atria Δ AERP (ms) * * * * * Blaauw et al, Circulation Oct QT-time AERP 400 ms Time (min) AVE 0118 (3mg/kg/h) ‘Early’ Class III Drugg AVE0118 (I Kur Blocker) Novel “Antiarrhythmic” Drugs for AF

33 Time (min) AF Termination (%) Vernalkalant (n=75/145) Placebo (n=3/75) 52% 4% For AF <7 days Odds of conversion=24 (95% CI, 7-84) Conversion rates for AF >7 days and AFL: 8% and 2.5%  RSD 1235  Phase 3 randomised plaebo- controlled trial  N=226, AF 3 h-7 d  N=116, AF 8-45 d  N=62, AFL  RSD mg/kg vs placebo  1 o EP: cardioversion within 90 min Roy et al. Circulation 2008, 117: No drug related torsades de pointes Vernakalant Hydrochloride for Conversion of AF Novel “Antiarrhythmic” Drugs for AF

34  Blocker Antiarrhythmic Agents New Class III Agents Novel Drugs TedisamilAzimilide Dronedarone Adenosine Agonist SAC Blockers ARDAs Na+/Ca2+ Inhibitor Na+/H+ Inhibitors Substrate therapies Amiodarone Sotalol Class III Quinidine Flecainide Class IC Multi-channel blockers Connexin modulators ARDAs (Vernakalant, AVE0118) Ranolazine “Antiarrhythmic” Drugs for AF Savelieva and Camm, Europace 2008;  Blocker ACEI ARB Statins PUFAs Pirfenidone Dofetilide Disopyramide Propafenone Class IA

35 Cumulative incidence HR=0.80 p= %CI=[0.59; 1.09] Placebo Dronedarone 400 mg BID Singh BN et al, NEJM 2008 Time to First CV Hospitalization or Death EURIDIS and ADONIS Meta-analysis Time(days) ? ATHENA Few adverse events ADONIS (N=630, follow-up 1 year) Log-rank test results: p= Cumulative Incidence Time (days) Time to AF Recurrence Dronedarone (Post-Hoc Analysis) New “Class III” Agents for AF Placebo Dronedarone 400 mg BID Hohnloser. Presented at Heart Rhythm Society 2008; May 2008; San Francisco, CA (A).

36 N=4628 patients with a history of paroxysmal or persistent AF Age ≥ 75 years with or without additional risk factors Age ≥ 70 years and ≥ 1 risk factor (hypertension, diabetes, prior stroke/TIA, LA ≥ 50 mm, LVEF ≤.40) R Dronedarone (400 mg bid)Placebo Phase III RCT: Minimum follow-up 12 months Primary EP: time to Death or Cardiovascular Hospitalisation J Cardiovasc Electrophysiol. 2008;19: ATHENA and Trial Design New “Class III” Agents for AF

37 ATHENA: Patient Characteristics Placebo (N=2327) Dronedarone (N=2301) Age (yrs)72+/-9 Female gender 45%49% AF at baseline 25% Structural Heart Disease 61%58% 32%29% Valvular Heart Disease16%17% Coronary Heart Disease NYHA III/IV 22%20% EF<0.35 4% Lone AF6% Arterial Hypertension 86%87% New “Class III” Agents for AF

38 ATHENA: Baseline Medications Placebo (N=2327) Dronedarone (N=2301) Betablocker71% Ca-antagonists 13%14% Digoxin 13%14% ACE/ARB 69%70% 60%61% Aspirin44% Vit.K anatagonists Statins 39%38% New “Class III” Agents for AF

39 Time to first cardiovascular hospitalization or death Mean follow-up 21  5 months. Hohnloser. Presented at Heart Rhythm Society 2008; May 2008; San Francisco, CA (A). Patients at risk Placebo Dronedarone Cumulative Incidence (%) HR=.76 P<.001 Months Placebo Dronedarone ATHENA: Primary Outcome New “Class III” Agents for AF

40 Outcome Placebo (N=2327) Dronedarone (N=2301) Hazard Ratio95% CIP Value All death Non-CV death CV death Cardiac non-arrhythmic death Cardiac arrhythmic death Vascular non-cardiac Hohnloser. Presented at the Heart Rhythm Society. May San Francisco, California (A). ATHENA: Fatal Outcomes New “Class III” Agents for AF

41 Outcome Placebo (N=2327) Dronedarone (N=2301) Hazard Ratio95% CIP Value Primary outcome <.001 First hospitalization for CV reasons <.001 AF <.001 CHF ACS Syncope Ventricular arrhythmia or non-fatal cardiac arrest Hohnloser. Presented at the Heart Rhythm Society. May San Francisco, California (A). ATHENA: Non-Fatal Outcomes New “Class III” Agents for AF

42 ATHENA: Summary Dronedarone Significantly Prolongs Time to Cardiovascular Hospitalisation or Death in Moderate to High Risk Elderly AF Pts All Cause Mortality was Not Increased in Pts Receiving Dronedarone Cardiovascular Mortality (Specifically Arrhythmic Death) was Lower in the Dronedarone Compared to the Placebo Group The Reduction in CV Hospitalisation was Mainly Due to Fewer Admissions for AF and Acute Coronary Syndromes Discontinuation of Study Drug Was Similar in Both Groups Indicating Good Tolerability of Dronedarone The Development Portfolio of this Drug is Practically Complete New “Class III” Agents for AF

43 Increased Mortality after Dronedarone Therapy for Severe Heart Failure New “Class III” Agents for AF ANDROMEDA Study; Kober et al. NEJM 2008, 358: After inclusion of 627 patients (310 in the dronedarone group and 317 in the placebo group), the trial was prematurely terminated beacuse of increased early mortality related to the worsening of heart failure

44  Blocker Antiarrhythmic Agents New Class III Agents Novel Drugs TedisamilAzimilide Dronedarone Adenosine Agonist SAC Blockers ARDAs Na+/Ca2+ Inhibitor Na+/H+ Inhibitors Substrate therapies Amiodarone Sotalol Class III Quinidine Flecainide Class IC Multi-channel blockers Connexin modulators ARDAs (Vernakalant, AVE0118) Ranolazine “Antiarrhythmic” Drugs for AF Savelieva and Camm, Europace 2008;  Blocker ACEI ARB Statins PUFAs Pirfenidone Dofetilide Disopyramide Propafenone Class IA

45 AF Disease Hypertension, heart failure AA effects (anti-fibrotic, antiarrhythmic?) Aldosterone antagonists Lipid-lowering effects Antiarrhythmic effects n-3 PUFA (fish oil) Reduction of BP, CHF MI, etc. Antiarrhythmic effects Beta blockers Anti-inflammatory effects Corticosteroids Coronary artery disease Systemic atherosclerosis AA effects (anti- inflammatory, antioxidant) Statins Hypertension Heart failure AA effects (anti-fibrotic, antiarrhythmic?) ACE inhibitors and ARBs Therapies Possible Target Substrate Prevention of Atrial Remodeling Atrial Remodeling Substrate Therapies for AF Targets: -Prevention of Heart Disease -Prevent HD-induced Remodeling -Prevent AF-induced Remodeling

46 SR (%) Years ACE Inhibitors Prevention of AF by Treating Heart Failure (Primary Prevention) Vermes et al, Circulation 2003;107;2926 Placebo (24% AF) Enalapril (5% AF) AR Antagonists Maggioni et al, Am Heart J 2005;149:548 Valsartan (5.1% AF) Placebo (8% AF) FU 2.9yFU 23m Cumulative Incidence of AF Months (SOLVD)(ValHeFT) Substrate Therapies for AF

47 With the courtesy of H Crijns Prevention of AF by Treating Heart Failure (Primary Prevention) Substrate Therapies for AF

48 Savelieva I & Camm AJ, not published. AF populations 80 Patients with hypertension (%) PIAF RACE STAF HOT CAFÉ AFFIRMpredominant AFFIRMoverall Prevention of AF by Treating Arterial Hypertension Substrate Therapies for AF

49 Fogari et al Journal of Cardiovasc. Pharmacol 2006 N=250 Mild AHT and Documented AF in Previous 6 months Amiodarone Losartan 50mg Amiodarone Amlodipine 5mg Prevention of AF by Treating Hypertension (Secondary Prevention) Substrate Therapies for AF

50 LIFE, Kjeldsen et al, JAMA, 2002; 288:1491 Stroke (%) Months Atenolol Losartan Wachtell et al, JACC; 2005; 45 New Onset AF (%) RR: 0.67 [95% CI: ], p< Months Atenolol Losartan Prevention of AF by Treating Hypertension (Primary Prevention) Substrate Therapies for AF

51 Natural Hx and Progression of AF Study# ptsFollow-upProgression UK general practice, st PAF age yrs 2.7 yrs; 1606 person- yrs 70/418 (17%) progression increased risk of mortality 1.5 ( ) Tokyo study, new onset PAF1 year 30/137 (22%) CARAF, men, 339 women 1 st AF 4.14 yrs 19%; time to progression 1138 days (men), 1092 days (women) CARAF, new onset PAF8 (2-11) yrs 8.6% by 1 year; 25% by 5 yrs; probability of any AF 63% by 5 yrs Danish study, st PAF9 (0-24) yrs 141 (33%) Parkinson, PAF10 yrs25% Tokyo study, PAF14 yrs 132/171 (77%) (5.5%/year Prevention of Progression of AF (No Structural Heart Disease) Substrate Therapies for AF

52 Days Amiodarone+ Irbesartan SR (%) Amiodarone P:0.007 * After ECV of Persistent AFIn Paroxysmal AF Yin et al, Eur Heart J 2006;27;1841 Amiodarone+ Losartan Amiodarone P:0.006 SR (%) Days Madrid et al, Circulation 2002;106:331 Secondary Prevention in The Absence of Heart Disease Substrate Therapies for AF

53 Willing/able to take OAC Yes Dose-adjusted OAC (INR 2.0–3.0) Clopidogrel (75 mg/d) + ASA (75–100 mg/day) Clopidogrel (75 mg/day) + ASA (75–100 mg/day) Placebo + ASA (75–100 mg/day) Placebo n = ACTIVE W ACTIVE A ACTIVE I R R R Patients with AF Irbesartan (150–300 mg/day) No Primary endpoint: Stroke, MI, CV death, Systemic Emboli ACTIVE Study ACTIVE Investigators, Lancet 2006;367: Substrate Therapies for AF

54  Atrial fibrillation will become much more common  Conventional therapies are only modesty effective  New “safer” variations of conventional therapies are almost available  Drugs with novel antiarrhythmic actions are in development  New targets that prevent substrate development or suppress triggers will become available  The rate versus rhythm debate will reignite  Mortality and morbidity will improve AF During the Next Half Decade Pharmacological Prevention of AF


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