Le bon usage des antiarythmiques dans la FA Prof. Christophe Scavée Responsable de l’Unité de Rythmologie Cliniques Universitaires St. Luc Vous souvenez-vous la fois où vous aviez oublié de réfléchir ?
Archives of Cardiovascular Disease (2010) 103, 376—387
Archives of Cardiovascular Disease (2010) 103, 376—387
Archives of Cardiovascular Disease (2010) 103, 376—387
RealiseAF → large discrepancy between published guidelines and current practice ! • N=10.523 , mean age 64.7, ≥1 AF episode, 26 countries • Tambocor, Rythmonorm in 589 patients (11.9%) – In 20.0%, indication not consistent with guidelines. • Sotalol in 4,4% – 16.0% indication not consistent with guidelines. • Amiodarone prescribed as first-line therapy in 25.6% – 50% no HF/HTA and LVH.
Current guidelines from the American College of Cardiology/ American Heart Association/European Society of Cardiology Associated disease 1 TE risk 2 AF type 3 Upestream therapy 4 GP 5x/y, Cardiologist 3x/y*
• Most AF patients may benefit from rhythm control strategy (SR) – ↗ quality of life – ↘ the risk of further structural remodeling caused by uncontrolled AF AAR therapy should only be offered to control resistant symptoms due to recurrent AF
Factors impacting survival in pts with AF AFFIRM investigators. Circulation 2004; 109: 1509-13
AF is Classified by Episode Duration and the Ability to Return to Sinus Rhythm 1st Detected Recurrent if ≥ 2 episodes Paroxysmal Persistent (self terminating - (not self terminating) usually within 7 days) Permanent (Refractory to cardioversion and/or accepted) ACC/AHA/ESC 2006 guidelines J Am Coll Cardiol 2006;48:854-906
AF is Classified by Episode Duration and the Ability to Return to Sinus Rhythm 1st Detected Recurrent if ≥ 2 episodes Paroxysmal Persistent (self terminating - (not self terminating) usually within 7 days) Permanent (Refractory to cardioversion and/or accepted) ACC/AHA/ESC 2006 guidelines J Am Coll Cardiol 2006;48:854-906
• Indication of AAR – Conversion of AF to SR – Facilitating successful electrical CV – For maintaining SR after cardioversion – Prophylaxis of AF
ACC/AHA/ESC Recommendations for Patients with Recurrent Paroxysmal AF RECURRENT PAROXYSMAL AF Minimal or no symptoms Disabling symptoms in AF Anticoagulation and rate Anticoagulation and rate control as needed control as needed AAD therapy No drug for prevention of AF Propaf./fleca « pill in the pocket » (Class Iia, Level of evid B) AF ablation if AAD treatment fails ACC/AHA/ESC 2006 guidelines J Am Coll Cardiol 2006;48:854-906 13
ACC/AHA/ESC Recommendations for Patients with Recurrent Persistent or Permanent AF RECURRENT PERSISTENT AF PERMANENT AF Anticoagulation and rate Disabling symptoms in AF Minimal or no symptoms control as needed Anticoagulation and Anticoagulation and rate control as needed rate control AAD therapy Electrical cardioversion AAD therapy/ATCO as needed Consider ablation for severely Cardioversion (shock) symptomatic recurrent AF after failure of ≥ 1 AAD ACC/AHA/ESC 2006 guidelines J Am Coll Cardiol 2006;48:854-906
Vaughan-Williams classification • AADs have distinct characteristics depending on which ion channels they block CLASS IV CLASS III CLASS I CLASS II Vaughan Williams EM. J Clin Pharmacol . 1984 ;24(4):129-47 15
Class Agents Metabolism Max dose 250-400/d (divided in Disopyramide Renal/hepatic 3-4 t.)- *SR250mg Class Ia 100,250mg CYP3A4 ↘ dose (renal/ hepatic dysfunction) Fleca Flecainide Fleca: Renal/hepatic 50–100 mg/12h 100, 150, 200mg CYP2D6 (genetically maximum dose 300– I.V. 150mg absent in 7-10%) Classe Ic 400 mg/d.*SR Apocard Propa Propafenone Propa: Hepatic 400-600mg (divided in 150,225,300mg CYP2D6, P-gp 3-4 t.) 80mg/12h Sotalol Class III Renal maximum dose 80, 160mg 160mg/12h Amiodarone oral load 10 g 200mg over 7–10 d, then 400 Hepatic I.V. 150mg mg for 3 wk then 200 mg/d *Sustained release
Efficacy and Risk of proarrhythmia 403 patients 100 Amiodarone 80 84% 69% % Sinus Rhythm 60 Propafenone 55% 40 Sotalol 39% 20 0 30 0 100 200 300 400 500 600 Time (days) P atients remaining in normal sinus rhythm on amiodarone vs propafenone or sotalol is plotted against the days of follow up. New England Journal of Medicine. Roy et al. 342 (13) page 913.
A4 Study: Freedom from AF Recurrence Ablation group (n=53): 89% (Mean of 1.8 ± 0.8 procedures) AAD group (n=55): 23% (Mean of 2.5 ± 1.0 AAD / patient) Jais et al, Circulation 2008;118:2498-2505
R/ AAR durations ? • AAR in AF generally been given as long-term therapy (months, years…)… • Short-term (4 w. post cardioversion) may ↘ R/ durations…?
Short-term versus long-term antiarrhythmic drug *The Flec SL trial N= 81 N= 273 N= 281 ST covers 80% of the LT strategy effect ! *Kirchhof P, The Lancet July 2012
AFFIRM – “On Treatment-Type” Analysis Sinus Rhythm -47% 0.53 (0.39 – 0.72; p <0.0001) Warfarin -50% 0.50 (0.37 – 0.69; p <0.0001) 1.49 (1.11 – 2.01; p = 0.0005) +49% AA Drugs 0 0,5 1 1,5 2 Mortality Risk Ratio Circulation 2004; 109:1509
ESC Guidelines 2012 • Guidelines (ESC/AHA) recommend that the choice of a rate vs. rhythm control strategy should be guided by the patient’s symptoms, as rhythm control has shown no survival benefit over rate control, and places patients at higher risk of drug- related adverse events and hospitalizations. AAR efficacy confirmed by trials BUT signals of concern related to adverse events and mortality
Cardiac/extracardiac toxicity Extracardiac Precautions Class Agents Cardiac effects effects and C.I. Glaucoma Bronchospasm, urinary Class Ia Disopyramide TdP fatigue retention hypoglycaemia VT, Fleca: dizziness, Afl 1:1 AV headache, visual Ischaemic or Flecainide conduction Classe Ic blurring structural Propafenone Unmask BS Propa: metallic heart disease HF taste, dizziness (-)inotropic effects ↘ dose 1/d if TdP (2-3%) CrCl 40- HF Class III Sotalol 60ml/min Bradycardia (25%) CI: CrCl is <40 Hypotension mL/min. Pulmonary toxicity hypo/er-thyroidism Amiodarone TdP (<1%) hepatic toxicity corneal deposits optic neuropathy skin
Benefits of AADs offset by side effects • The most important pro-arrhythmias = TdP !!! – Potentially life-threatening arrhythmia → VF – +++ with Vaughan-Williams class Ia/pure class III AADs • 2-3% with d-l sotalol, but 0,7% amiodarone – Caused by a ↗of QTc (block of Ikr)
Torsades de Pointes • Occurs predominantly within the first 3 days of R/ • R/should (?) be – Ideally initiated [FDA] in HOSPITAL (monitoring) – Or as an outpatient at low dosage (sotalol 80 2x) • ECG-controlled • Up-titration of therapy (every 3-5d.) and ECG control – ECG confirms no clinically significant QT ↗ – QT prolonged generally ≥450 ms (+10-40ms with sotalol). » Sotalol “dose dependent” !!! HYPOKALIEMIA » Low risk with amiodarone (consider max QTc 500ms)
Torsades de Pointes • The risk of TdP precludes – The use of class IA/‘pure’ class III agents • And – Left ventricular hypertrophy – Bradycardia – Medical history/family history of LQTS *15% of pts with the acquired LQT – Heart failure, ischaemic heart disease syndrome have DNA – Black race variance in the coding regions of genes – Female known to code for congenital LQTS. – ↘creatinine clearance – History of ventricular arrhythmias – Electrolyte disorders (hypokalaemia/hypomagnesaemia) *Yang P, et al. Frequency of ion channel mutations and polymorphisms in a large population of patients with drug- associated long QT syndrome. Program and abstracts of the North American Society of Pacing and Electrophysiology 22nd Annual Scientific Sessions; May 2-5, 2001; Boston, Massachusetts. Abstract 164.
Others pro-arrhythmias • Class Ic • PR ↗ • QRS duration ↗ (15% when flecainide) • Flutter 2/1, 1/1 • Cardiac depression → VT (post IDM scar)
Metabolism/interactions • Class Ic – Flecainide • Plasma level – Goal trough level 0,2-1mcg/ml • Dose ↘ 50% if the GFR is ≤50ml/min • If used concomitantly with digoxin, the digoxin dose should be ↘ by ~ 25% – Propafenone: ↗[AVK and digox ]
Extracardiac effects of amiodarone • Amio contains 37% iodine by weight (200mg = 70mg iode) • 14–18% of pts with long-term R/ affected with both hypothyroidism/hyperthyroidism • Pulmonary fibrosis : 1-2% • Dose dependent, onset weeks-years • Liver toxicity: 1-2%
Extracardiac effects • Amiodarone • Pulmonary-function tests, thyroid-function tests, liver- function tests, and chest RX recommended at baseline, at 3, 6, and 12 months, and annually • Eye examination performed annually.
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