Prof. Christophe Scave Responsable de lUnit de Rythmologie - - PowerPoint PPT Presentation

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.

Associated disease TE risk AF type Upestream therapy

1 2 3 4

Current guidelines from the American College of Cardiology/ American Heart Association/European Society of Cardiology

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

Permanent

(Refractory to cardioversion and/or accepted)

Persistent

(not self terminating)

Paroxysmal

(self terminating - usually within 7 days)

1st Detected

ACC/AHA/ESC 2006 guidelines J Am Coll Cardiol 2006;48:854-906

Recurrent if ≥2 episodes

AF is Classified by Episode Duration and the Ability to Return to Sinus Rhythm

Permanent

(Refractory to cardioversion and/or accepted)

Persistent

(not self terminating)

Paroxysmal

(self terminating - usually within 7 days)

1st Detected

ACC/AHA/ESC 2006 guidelines J Am Coll Cardiol 2006;48:854-906

Recurrent if ≥2 episodes

• Indication of AAR

–Conversion of AF to SR –Facilitating successful electrical CV –For maintaining SR after cardioversion

– Prophylaxis of AF

13

ACC/AHA/ESC Recommendations for Patients with Recurrent Paroxysmal AF

ACC/AHA/ESC 2006 guidelines J Am Coll Cardiol 2006;48:854-906

RECURRENT PAROXYSMAL AF

Disabling symptoms in AF Minimal or no symptoms Anticoagulation and rate control as needed Anticoagulation and rate control as needed No drug for prevention of AF

AAD therapy

AF ablation if AAD treatment fails

Propaf./fleca « pill in the pocket » (Class Iia, Level of evid B)

ACC/AHA/ESC Recommendations for Patients with Recurrent Persistent or Permanent AF

ACC/AHA/ESC 2006 guidelines J Am Coll Cardiol 2006;48:854-906

RECURRENT PERSISTENT AF PERMANENT AF

Disabling symptoms in AF Minimal or no symptoms Anticoagulation and rate control as needed Anticoagulation and rate control Electrical cardioversion as needed Anticoagulation and rate control as needed Consider ablation for severely symptomatic recurrent AF after failure of ≥ 1 AAD

AAD therapy

AAD therapy/ATCO

Cardioversion (shock)

15

Vaughan-Williams classification

• AADs have distinct characteristics depending on which ion channels

they block

Vaughan Williams EM. J Clin Pharmacol. 1984 ;24(4):129-47

CLASS II CLASS III CLASS IV CLASS I

Class

Agents Metabolism Max dose

Class Ia

Disopyramide 100,250mg Renal/hepatic CYP3A4 250-400/d (divided in 3-4 t.)- *SR250mg ↘ dose (renal/ hepatic dysfunction)

Classe Ic

Flecainide 100, 150, 200mg I.V. 150mg Propafenone 150,225,300mg Fleca: Renal/hepatic CYP2D6 (genetically absent in 7-10%) Propa: Hepatic CYP2D6, P-gp Fleca 50–100 mg/12h maximum dose 300– 400 mg/d.*SR Apocard Propa 400-600mg (divided in 3-4 t.)

Class III

Sotalol 80, 160mg Renal 80mg/12h maximum dose 160mg/12h Amiodarone 200mg I.V. 150mg Hepatic

• ral load 10 g
• ver 7–10 d, then 400

mg for 3 wk then 200 mg/d

*Sustained release

Efficacy and Risk of proarrhythmia

100 80 60 40 20 Time (days) % Sinus Rhythm Amiodarone 600 500 400 300 200 100 Sotalol Propafenone

69% 39%

403 patients 30

55% 84%

Patients 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

Jais et al, Circulation 2008;118:2498-2505

Ablation group (n=53): 89% AAD group (n=55): 23% (Mean of 1.8 ± 0.8 procedures) (Mean of 2.5±1.0 AAD / patient)

R/ AAR durations ?

• AAR in AF generally been given as long-term

therapy (months, years…)…

• Short-term (4 w. post cardioversion) may ↘ R/

durations…?

*The Flec SL trial

N= 81 N= 273 N= 281

ST covers 80% of the LT strategy effect !

*Kirchhof P, The Lancet July 2012

Short-term versus long-term antiarrhythmic drug

AFFIRM – “On Treatment-Type” Analysis

0,5 1 1,5 2 Mortality Risk Ratio

Sinus Rhythm Warfarin AA Drugs

0.53 (0.39 – 0.72; p <0.0001) 0.50 (0.37 – 0.69; p <0.0001) 1.49 (1.11 – 2.01; p = 0.0005)

• 47%
• 50%

+49%

Circulation 2004; 109:1509

ESC Guidelines 2012

AAR efficacy confirmed by trials BUT signals of concern related to adverse events and mortality

• 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

• ver rate control, and places patients at higher risk of drug-

related adverse events and hospitalizations.

Cardiac/extracardiac toxicity

Class

Agents Cardiac effects Extracardiac effects

Precautions and C.I.

Class Ia

Disopyramide TdP

Bronchospasm, fatigue Glaucoma urinary retention hypoglycaemia

Classe Ic

Flecainide Propafenone VT, Afl 1:1 AV conduction Unmask BS HF (-)inotropic effects Fleca: dizziness, headache, visual blurring Propa: metallic taste, dizziness Ischaemic or structural heart disease

Class III

Sotalol TdP (2-3%) HF Bradycardia (25%) Hypotension

↘ dose 1/d if CrCl 40- 60ml/min CI: CrCl is <40 mL/min.

Amiodarone TdP (<1%)

Pulmonary toxicity hypo/er-thyroidism hepatic toxicity corneal deposits

• ptic neuropathy skin

• 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)

Benefits of AADs offset by side effects

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 – Heart failure, ischaemic heart disease – Black race – Female – ↘creatinine clearance – History of ventricular arrhythmias – Electrolyte disorders (hypokalaemia/hypomagnesaemia)

*15% of pts with the acquired LQT syndrome have DNA variance in the coding regions of genes known to code for congenital LQTS.

*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.

Take Home Message

• Dans la FA paroxystique et persistante les AAR ont montré leurs efficacités à

restaurer et maintenir le RS. Il n’y a aucun effet (+) sur le risque d’AVC ou la mortalité.

• La prescription de ces substances passe par des prérequis:

– Statut cardiaque, fonction rénale, ionogramme, possibles interactions médicamenteuses doivent être connus du prescripteur.

• Des complications sérieuses, voire mortelles ont été directement reliées à

l’utilisation de ces substances et doivent maintenir le prescripteur attentif aux plaintes du patient. Commencer par de petites doses !

• Dans certains cas l’ablation par radiofréquence est le traitement de choix.

Merci pour votre attention

Back-up

Site of action

• SAN, atrium

– Ia eg quinidine, disopyramide – II beta blockers – III eg amiodarone – IV ? Verapamil – ? digoxin

Site of action

• AVN
• - Ia ? disopyramide
• Ic eg flecainide
• II beta blockers
• III amiodarone
• IV verapamil
• digoxin

Site of action

• Anomalous pathway
• - Ia disopyramide, quinidine
• Ic flecainide (most effective)
• III amiodarone

AAR

• Ia

– quinidine, procainamide, disopyramide

• - ↗ action potential
• ↘ rate of rise of phase 0
• ↗ repolarization
• ↗ refractoriness by blocking several types of

potassium channel

• ↗ PR, QRS, QT
• moderate-marked sodium channel blockade

AAR

• Ib

– lidocaine, mexilitine, phenytoin, propafenone

• - ↘ action potential
• limited effect on rate of rise of phase 0
• ↘ repolarization
• ↘ QT
• Raise fibrillation threshold
• Mild-moderate sodium channel blockade
• Little effect on refractoriness since there is

essentially no blockade of potassium channels

AAR

• Ic
• flecainide

– no effect on length of action potential

• markedly ↘ rate of rise of phase 0
• little effect on repolarization
• markedly ↗ PR and QRS
• marked Na channel blockade
• prolong refractoriness by blocking outward-

rectifying potassium channels

AAR

• II
• Beta-blokers
• ↘ potential for arrhythmias to develop in response to

catecholamines

• eg bretylium: blocks release of sympathetic transmitters
• beta blockers: competitive antagonists and also block

possible arrhythmogenic effect of cAMP

• indirect blockade of Ca channel opening by attenuating

adrenergic activation

AAR

• IV
• calcium channel blockers
• inhibit slow inward calcium mediated current and depress

phase 2 and 3

• slow SAN pacemaker cells and AVN conduction by direct

blockade of Ca channels

• have inportant effects on upper and middle parts of the AV

node

• may have particular value in blocing one limb of a re-entry

circuit

Drug interactions

• Most AAD metabolised by the cyt. P450.
• Some interact with drugs through (-) of the P-

glycoprotein system.

• Excreted in the urine (sotalol)

A.J. Camm. International Journal of Cardiology 127 (2008) 299–306

Teratogenic Effects

• Sotalol

– cross the placenta, and is found in amniotic fluid – Sotalol should be used during pregnancy only if the potential benefit outweighs the potential risk. – Pregnancy category B

Teratogenic Effects

• Amiodrone

– pregnancy category D – Amiodarone should only be given during pregnancy when there are no alternatives and benefit outweighs risk. – Amiodarone and its metabolite cross the human placenta – Amiodarone is excreted into human milk.

Teratogenic Effects

• Flecainide

– assigned to pregnancy category C – Excreted in the human milk

• Flecainide is considered compatible with breast-feeding

by the American Academy of Pediatrics.

Sotalol an kidney function

http://www.drugs.com/pro/sotalol.html

http://www.drugs.com/pro/sotalol.html