Role of class 1C AAD revisited

Transcription

1 Role of class 1C AAD revisited Juan Tamargo Department of Pharmacology, School of Medicine Universidad Complutense, Madrid, Spain Conflict of interest: I am a Pharmacologist

2 Prevalence of AF in Spain OFRECE study (Gómez-Doblas et al. Rev Esp Cardiol 2014;67: ) 1. The age-adjusted prevalence was 4.45% (17.7% in > 80 años) 2. Around patients with AF (over undiagnosed) 3. Less than 1% undergoes a non-pharmacological treatment What to do with the other 99,2% of patients? What to do with those who remain in AF after ablation(s)? What about those who are not suitable for ablation? Administer AADs even when they are modestly Men Women Total effective and can produce serious AEs

3 Brief history of class I AADs Quinidine Digitalis Verapamil Propranolol 1965 Bretilium Diltiazem Lidocaine Procainamide 1956 Ajmaline 1962 Disopyramide 1967 Amiodarone CAST, Mexiletine 1973 Aprindine, Tocainide Flecainide Propafenone Ibutilide Dofetilide 2009 Dronedarone Vernakalant

4 Flecainide and propafenone - MOA Potent Na + channel blockers (active state) Frequency- and voltage-dependent inhibition Slow intracardiac conduction (H-P), reduce excitability Prolong channel recovery from inactivation ( AERP/APD: posrepolarization refractorines) They supress cardiac automaticity and triggered activity Block (I to, I Kr, I Ks, I KAch ) or activate (I K1 ) K + channels Prevent abnormal cardiac RyR2 receptor-mediated Ca 2+ release Propafenone: weak -receptor and I Ca,L and blocker (PM) Prolong the PR, QRS, or QT intervals Modest negative inotropic effects (IV, in patients with LV dysfunction or HF) Recomendations Class Level ECG recording during the initiation of AAD therapy should be considered to monitor HR and detect QRS and QT interval prolongation or AV block on days 1-3 in patients receiving flecainide or propafenone IIa B

5 Flecainide prolongs atrial APD and refractoriness at fast rates (Wang et al. Circ Res 1992;71: ) Reverse usedependence 1. Flecainide has no effect on QT interval, but produces a rate-dependent prolongation in atrial APD and refractoriness (exerts a class III effect) Slows the recovery kinetics of Na + channels at fast rates

6 Flecainide prolong atrial cycle length and refractoriness and induces atrial postrepolarization refractorines in patients with persistent AF APD90 = ms AERP = ms Kirchhof P et al. Basic Res Cardiol 2005;100:

7 Flecainide flecainide blocks ryanodine (RyR2) channels, reduces Ca 2+ wave frequency and prevents CPVT Watanabe et al. Nat Med 2009;15:380-3.

8 Prevention of thromboembolism Ventricular rate control PCV to SR Rhythm control strategy Restore normal SR pharmacological cardioversion Facilitate electrical cardioversion Prevent recurrences of AF after Cardioversion/Ablation Short time Long time

9 1. Acute restoration of sinus rhythm (PCV) Recomendations Class Level In selected patients with recent-onset AF and no significant structural or ischaemic heart disease, a single oral dose of flecainide of propafenone (PiP pproach) should be considered for patient-led cardioversion, following safety assessment IIa B

10 Conversion rates of recent-onset AF AADs are more effective when initiated within 2 days Cumulative conversion rates (%) of AF ( 48 hrs) in relation to the time after infusion * < 24 hrs 2-7 days > 8 days Window remodeling IC AADs SR is restored in 60-70% within 2 h Amiodarone - slower onset of CV Lower risk of proarrhythmia First choice in patients with HF or CAD Reisinger J. Am J Cardiol 1998;81:1450 Martinez-Marcos Am J Cardiol 2000;86:

11 Flecainide recovers its antiarrhythmic action after cardioversion of AF (MEDCAR Study) Conversion to SR (%) Conversion to SR (%) 181 patients with persistent AF (median duration 3 months) <0.001 NS NS < < 4 ds 4-8 ds > 8 ds hs 5-10 hs > 10 hs Duration of SR post ECV Duration of 2nd AF episode Success in relation to duration of SR after the previous ECV Tieleman RG. Heart Rhythm 2005: Success in relation to duration of the 2nd episode of AF in patients in SR >4 days after ECV

12 2. Prevent recurrences of AF after successful ECV/ablation Electrical CV/ablation is not always successful in inducing/ maintaining SR Short-term treatment with AADs an avoid early recurrences after ECV/ablation It would increase drug safety by reducing treatment duration Intermediate recurrence 5 min 4 weeks Van Gelder et al. AJC 1999;84:147R-151R Recomendations Class Level Pre-treatment with flecainide or propafenone can improve the efficacy of electrical cardioversion and prevent recurrent AF IIa B

13 Short-term antiarrhythmic drug therapy 1. It may be useful: In patients at increased risk of proarrhythmia/adrs 2. Treatment with flecainide after successfull ECV of persistent AF is welltolerated, reduces symptoms and prevents most (80%) AF recurrences (1) 3. A meta-analysis of the available (weak) evidence suggests slightly better prevention of recurrent AF in patients treated with AADs after catheter ablation (2) Prospective CTs are needed (1) Kirchhof P et al. Lancet (2) Calkins H et al. Circ Arrhythm Electrophysiol 2009

14 3. Initiation of long-term rhythm control therapy in symptomatic patients with AF

15 Class IC AADs for maintaining sinus rhythm after cardioversion of AF AF recurrence Studies all class IC 1. Determine inpatients who have recovered SR affter having AF, the effects of long-term treatment with AADs on recurrence of AF, death, stroke, embolism and adverse effects 2. Class IC (flecainide, propafenone) AADs significantly reduced recurrence of AF (NNT to beneft 4-5) Clinically successful AAD therapy reduces rather than eliminate the recurrences of AF Lafuente-Lafuente et al. Cochrane Database of Systematic Reviews 2015:CD005049

16 Class IC AADs Specific clinical indications Pulmonary diseases: flecainide is safe. Propafenone is contraindicated in patients with bronchospasm (safe in long-standing chronic obstructive lung disease) WPW and Pre-excited AF: IV propafenone (procainamide) to acutely slow heart rate Sports: after PiP flecainide or propafenone, patients should refrain from sports as long as AF persists and until 2 half-lives of the ADD have elapsed (IIa, C) Pregnancy: flecainide can be used for conversion of fetal arrhythmias without major ADRs and is safe to treat maternal symptomatic AF POAF: It is reasonable to administer AADs to maintain SR with recurrent or refractory POAF (IIa, B) January et al. JACC 2014 (AHA/ACC/HRS); Kirchhof et al. Eur Heart J 2016 (ESC/EACTS)

17 Selection of AADs should be based on SAFETY Symptom relief Safe AAD Reduced CV morbidity & mortality Recomendations The decision to initiate long-term AAD therapy needs to be carefully evaluated, taking into account the presence of comorbidities, CV risk and potential for serious proarrhythmia, extracardiac toxic effects, patient preferences, and symptom burden. Class Level I A

18 Antiarrhythmics for maintaining sinus rhythm after cardioversion of AF Overall mortality Class IA drugs (pooled data) significantly increased all-cause mortality at 1 year FU. They are less commonly used for rhythm control in AF. It is prudent lo limit their use to specific situations

19 AADs for maintaining SR after cardioversion of AF Withdrawals due to adverse effects and proarrhythmia All AADs increased withdrawals due to AEs (NNH 9-27) All AADs showed increased pro-arrhythmic effects with the exceptions of amiodarone, dronedarone and propafenone

20 Kaplan Meier rates of hospitalization types in 9562 young patients with AF but without structural heart disease AF hospitalization CV hospitalization Non-AF/AFl CV hospitaliz. Amiodarone was associated with a significantly lower risk of AF and cardiovascular hospitalizations than Class IC AADs and sotalol; the risk was significantly greater for dronedarone than any of the other AADs No significant differences in AF or cardiovascular hospitalization between Class IC AADs and sotalol An increased risk of non-af/afl cardiovascular hospitalizations with amiodarone versus Class IC AADs. LaPointe et al. Circ Cardiovasc Qual Outcomes. 2015;8:

21 Kaplan Meier rate of discontinuation by initial AAD Dronedarone Amiodarone Class IC and Sotalol 8,562 patients <65 y, without SHD. Rates of discontinuation rate was 40% for class IC drugs, 52% for amiodarone, 40% for sotalol, and 69% for dronedarone LaPointe et al. Circ Cardiovasc Qual Outcomes 2015;8:

22 Class I AADs Safety considerations Drug NOT/Cautions Drug Interactions Flecainide Propafenone Sinus or AV node dysfunction QRS >25% baseline HF or CAD Infranodal conduction disease Brugada syndrome Renal or liver disease Asthma (P) Metabolized by CYP2D6 inhibitors Pc (amiodarone, quinidine, fluoxetine, paroxetine, quinidine, ritonavir, sertraline, TADs) Cimetidine and amiodarone Pc of flecainide Flecainide digoxin Pc PM: 7-10% of population Renal excretion Metabolized by CYP2D6 Increases the Pc of digoxin, metoprolol, propranolol and warfarin (INR) PM have beta-blockade CYP3A4 inhibitors (erythromyxin, ritonavir, saquinavir, or grapefruit juice) can increase propafenone Pc

23 Comorbidities represent an arrhythmogenic substrate and can modulate the efficacy/safety of AADs Idiopathic AF (10-30%) No evidence of cardiac disease Different In the context of another Secondary co-morbidities AF different substrates process different therapeutic strategies One size fits all approach is doomed to failure Treatment should be individualized Acute CV causes Structural heart disease Goal: to slow or arrest AF onset and progression No-Cardiovascular Myocardial infarction Hypertension Hyperthyroidism Cardiac surgery Coronary artery disease Diabetes Pericarditis Recomendations Class Level Heart failure Obesity/sleep apnea Management Inflammation of cardiovascular Cardiomyopathies risk factors and avoidance Pulmonary diseases of AF triggers should be pursued Valvular diseases in patients on rhythm Autonomic IIa nervous B system control therapy to facilitate Aging maintenance heart of sinus rhythm Drugs, alcohol Genetic determinants

24 Propafenone - New ongoing clinical trials Drug NCT/EU Phase NCT New formulations of propafenone to treat AF I/II NCT Propafenone Versus Amiodarone in Septic Shock (PRASE) IV NCT A clinical study of the arctic front cryoablation balloon for the treatment of paroxysmal AF (Stop-AF) NCT Antiarrhythmic drugs assessment in preventing AF (ADA-PAF) IV III NCT NCT NCT NCT Early Aggressive Invasive Intervention for Atrial Fibrillation (EARLY-AF) A study of the effectiveness of anti-arrhythmic medications after AF ablation Catheter ablation compared with pharmacological therapy for AF (CAPTAF) Therapy of Atrial Flutter by Afib Ablation (TripleA) NCT AV Node Ablation and Pacemaker Therapy Compared to Drug Therapy for Atrial Fibrillation - Pilot Study (PACIFIC) NCT Early Treatment of Atrial Fibrillation for Stroke Prevention Trial (EAST) IV NCT Ablation Verses Anti-arrhythmic Therapy for Reducing All Hospital Episodes From Recurrent Atrial Fibrillation (AVATAR-AF) NCT Kansai Plus Atrial Fibrillation Trial (KPAF) IV NCT NCT Comparison of brain perfusion in rhythm control and rate control of persistent AF Catheter ablation vs antiarrhythmic drugs for therapy of premature ventricular contractions in patients with structural heart disease (CAT-PVC)

25 Flecainide - Ongoing clinical trials Drug Title Phase NCT NCT NCT NCT NCT NCT Diagnostic Value and Safety of Flecainide Infusion Test in Brugada Syndrome Predictive factors to effectively terminate paroxysmal AF by blocking atrial selective ionic currents (SELECTCARFAP) PVC Suppression using Flecainide Catheter Ablation Compared With Pharmacological Therapy for AF (CAPTAF) Acute Cardioversion vs wait and see-approach for symptomatic Atrial Fibrillation in the Emergency Department (ACWAS) Therapy of Atrial Flutter by Afib Ablation (TripleA) NCT Early treatment of AF for stroke prevention trial (EAST) IV NCT NCT YouScript IMPACT (Improving Medication Protocols and Abating Cost of Treatment) Registry Management of AF with flecainide : the AFFLEC Study NCT FAST Therapy Trial of Fetal Tachyarrhythmia III NCT (EARLY-AF) NCT If PVI performed with the Arctic Front cryoballoon is superior to AAD as first-line therapy in preventing AF recurrences PV isolation with vs without continued aad treatment in subjects with recurrent AF (POWDER-AF) IV IV

26 Treatment of AF AADs remains the mainstay treatment AADs are here to stay 1. After 40 years, class IC AADs still have a role in the treatment of AF 2. Effective for cardioversion and maintaining SR after cardioversion Modest efficacy vs too late and in the wrong patient Contraindicated in the presence of structural heart diseas 2. We need to understand their MOA No much interest in understanding/developing AADs (high risk, low benefit) Clinical electrophysiologists do not like AADs, but ablation fails Several ablations of selected patients results at 5 years in.. GPs must treat patients with AADs 3. Gaps in Knowledge Most of the RCTs with class IC AAADs were performed many years ago Lafuente-Lafuente et al : NO data on relevant clinical outcomes (mortality, stroke, thromboembolism or remodeling) New perspectives in 2016 Guidelines on AF: Drug combinations (?) Hybrid therapy (poor information)