DECLARATION OF CONFLICT OF INTEREST. Consultant Sanofi Biosense Webster Honorarium Boehringer Ingelheim St Jude Medical

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1 DECLARATION OF CONFLICT OF INTEREST Consultant Sanofi Biosense Webster Honorarium Boehringer Ingelheim St Jude Medical

2 ESC Congress Paris, France August 27-31, 2011 Risk & Complications of AADs for Rhythm Control Antonio Raviele, MD, FESC, FHRS Cardiovascular Department, Ospedale dell Angelo, Mestre Venice, Italy

3 Vaughan Williams Classification / AA Drugs Type la Disopyramide Procainamide Quinidine Type IB Lidocaine Mexiletine Type IC Flecainide Moricizine Propafenone Type II Beta-blockers Type III Sotalol Amiodarone Dronedarone Bretylium Dofetilide Ibutilide Type IV Calcium antagonists

4 AADs / Risk & Complications Extracardiac Adverse Events Cardiac Adverse Events Proarrhythmia Negative inotropic effect Impact on Mortality Recommendations to avoid Risk & Complications Future Perspectives

5 Extracardiac side effects of Flecainide Adverse Reaction % of Patients Difficulty in visual accomodation 47% Dizziness / lightheadedness 42% Nausea 14% Headache 13% Fatigue 11% Tremor 8% Dyspnea 8% Diarrhea 6% Palpitation 6% Asthenia 6% Miscellanea ( 3 complaints) 36 pts ( ) None 20% Anderson JL et al. Circulation 1989;80:

6 Extracardiac side effects of Propafenone Adverse Reaction Gastrointestinal complaints Nausea / Vomiting Dyspepsia Constipation Neurologic disturbance Dizziness / lightheadedness % of Patients 15% 9% Metallic taste 4% Fatigue 1% Bellandi F et al. Am J Cardiol 2001;88:

7 Extracardiac side effects of Sotalol Adverse Reaction % of Patients Fatigue / Weakness 20% - 13% Dizziness / lightheadedness 20% - 12% Nausea / Vomiting 10% Edema 8% Sleep disturbances 8% Headache 8% Extremity pain 7% Diarrhea 7% Hypotension 6% Mental confusion 6% Anxiety / Depression 4% - 4% Impotence 2% Data from more published studies

8 Extracardiac side effects of Amiodarone Adverse Reaction % of Patients Hypothyroidism 6% Hyperthyroidism 0.9-2% Pulmonary toxicity 1-17%% Hepatotoxicity ( Enzyme levels) 15-30% Hepatotoxicity (Hepapatis / Cirrosis) <3% Corneal microdeposits >90% Optic neuropathy / Neuritis 1-2% Blue-gray skin discoloration 4-9% Photosensitivity 25-75% Tremor / Ataxia 3-35% Peripheral neuropathy 0.3% year Vassallo P, Trohman RG. JAMA 2007; 298:

9 Extracardiac side effects of Dronedarone Adverse Reaction % of Patients Gastrointestinal events 26.2% Diarrhea 9.7% Nausea 5.3% Abnormal liver function test 0.6% Neurologic events 16.3% Dizziness 7.4% Headache 3.1% Respiratory events 14.5% Dyspnea 5.2% Cough 3.6% Skin-related events 10.3% Hohnloser S et al. N Engl J Med 2009;360:

10 Direct meta-analysis safety summary results Comparison vs Placebo Treatment withdrawals (OR) Withdrawals due to AE (OR) Serious adverse events (OR) Proarrhythmia events (OR) Flecainide 2.92 ( ) 8.45 ( ) ( ) 6.60 ( ) Propafenone 1.55 ( ) 2.00 ( ) 2.12 ( ) 2.34 ( ) Sotalol 0.91 ( ) 2.06 ( ) 1.77 ( ) 2.21 ( ) Amiodarone 3.92 ( ) 8.41 ( ) 8.10 ( ) 2.27 ( ) Dronaderone 1.23 ( ) 1.63 ( ) 1.22 ( ) 1.46 ( ) Freemantle N et al. Europace 2011;13:

11 % Amiodarone Withdrawal CTAF PIAF AFFIRM 18% at 16 m 25% at 1 y 12.3% at 1 y

12 AADs / Risk & Complications Extracardiac Adverse Events Cardiac Adverse Events Proarrhythmia Negative inotropic effect Impact on Mortality Recommendations to avoid Risk & Complications Future Perspectives

13 Arrhythmic Events Total (n = 2033) Women (n = 771) Men (n = 1262) P Value Total subjects with event Cardiac arrest Torsades de pointe Systained VT Arrhythmic death 92 (5%) 34 (4%) 62 (5%) (0.79%) 4 (0.52%) 12 (1%) (0.59%) 7 (1%) 5 (0.4%) (0.25%) 0 (0%) 5 (0.4%) (4%) 27 (4%) 50 (4%) 0.60 Kaufman ES et al. J Am Coll Cardiol 2004; 44:

14 Proarrhythmic profile of antiarrhythmic drugs Drug Torsade de Pointe VF VT Atrial flutter 1:1 Brady arrhythmia Flecainide Rare Propafenone Rare Sotalol 2-5% Amiodarone <1% Dronedarone Rare Modified from Friedman PL et al. Am J Cardiol 1998; 82: 50N-58N

15 Effect of AADs on incidence of proarrhythmic events Freemantle N et al. Europace 2011;13:

16 AADs / Risk & Complications Extracardiac Adverse Events Cardiac Adverse Events Proarrhythmia Negative inotropic effect Impact on Mortality Recommendations to avoid Risk & Complications Future Perspectives

17 Preliminary report: Effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. N Engl J Med 1989; 321:

18 Effects of flecainide on all-cause mortality in post-mi CAST I : 2309 post-mi pts with LVEF <55%, half <40% 3.0% 7.7% CAST I N Engl J Med 1989; 321:

19 Adverse Events of the 3 Treatment Assignments. Connolly, S. J. et al. JAMA 2006;295:

20 N Engl J Med 1995; 333: 77-82

21 Singh SN et al. N Engl J Med 1995; 333: 77-82

22 during a median follow-up of 2 months, the mortality rate was 8,1% in the dronedarone group compared to 3.8% in the placebo group The trial was prematurely terminated due to an excess of mortality in the dronedarone group 8.1% 3.8% Kober L et al. N Engl J Med 2008;358:

23 Time to first cardiovascular hospitalization or death Risk 22% The results were similar to those of the overall population, with a relative risk reduction of 22% of the primary end-point of the study Hohnloser S H et al. Eur Heart J 2010;31:

24 Choice of antiarrhythmic drug according to underlying pathology. Camm AJ et al. Eur Heart J 2010;31:

25 AADs / Risk & Complications Extracardiac Adverse Events Cardiac Adverse Events Proarrhythmia Negative inotropic effect Impact on Mortality Recommendations to avoid Risk & Complications Future Perspectives

26 Overall Mortality associated with AADs Lafuente C et al. Arch Intern Med (2006) 166:

27 Implications The increased mortality of AADs due to their adverse effects probably nullifies the potential beneficial effects on survival of mantainance of sinus rhythm with these drugs.

28 Trial Rate vs Rhythm Trials n Age, y Mean Follow-up Sinus rhythm (%) Warfarin (%) Thrombo-embolic complications % Mortality % PIAF 12m Rate control Rhythm control NR NR AFFIRM 42m Rate control Rhythm control RACE 27m Rate control Rhythm control STAF 22m Rate control Rhythm control NR NR NR Hot Cafe 20m Rate control Rhythm control NR NR AF-CHF 37m Rate control Rhythm control J-RHYTHM 19m Rate control Rhythm control Modified from Falk, RH. Circulation (2005) 111: 3141

29 Incidence rates for deaths in all treatment groups and in the population receiving no antiarrhythmics patients hospitalized for AF in the period in Denmark Andersen S S et al. Europace 2009;11:

30 AADs & Mortality This suggests that, if AADs are selected on the basis of an appropriate risk stratification and individual patient evaluation, their use does not bring an increased risk of death

31 AADs / Risk & Complications Extracardiac Adverse Events Cardiac Adverse Events Proarrhythmia Negative inotropic effects Impact on Mortality Recommendations to avoid Risk & Complications Future Perspectives

32 AADs / Safety Recommendations (1) Adequate patient and physician education and awareness of the side effects of AADs Selection of the most appropriate AADs in the single patient based on a strict respect of current indications and contraindications Thorough baseline evaluation (with periodic reassessment) of liver, kidney, thyroid and other organs function

33 AADs / Safety Recommendations (2) In-hospital initiation of therapy in a monitoring setting in patients at high risk of proarrhythmia Drug titration with incremental increase of dosage to a level that provides the desired effect Evaluation of potential interactions with other drugs, especially in elderly people and patients with comorbidities Regular ECG monitoring during the follow-up

34 AADs / Risk & Complications Extracardiac Adverse Events Cardiac Adverse Events Proarrhythmia Congestive Heart Failure Effects on Mortality Recommendations to avoid Risk & Complications Future Perspectives

35 Novel AADs In the future, it is to be hoped that newer generation novel AADs now on the horizon, such as multichannel blockers, atrial-specific agents, and gap junction modulators, will prove to be not only highly efficacious, but also better tolerated with no or minimal side effects, compared to currently available AADs, offering better pharmacotherapy of AF

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