There are future perspectives in the pharmacological treatment of arrhythmias

Transcription

1 There are future perspectives in the pharmacological treatment of arrhythmias George Andrikopoulos, MD, PhD, FESC, Cardiologist, Director, 1st Department of Cardiology/ Department of Electrophysiology & Pacing, Henry Dunant Hospital Center, Athens, Greece

2 Presenter Disclosure Information The presenter has received honoraria for participation in lectures and advisory boards from the following pharmaceutical and biotechnology companies: o AstraZeneca, o Bard, o Bayer Healthcare, o Boehringer Ingelheim, o Boston Scientific, o Bristol-Myers Squibb, o ELPEN, o Galenica, o Lilly, o Medtronic, o Menarini, o MSD, o Pfizer, o Sanofi, o Servier, o StJude, o Unifarma, o Vianex.

3 VAUGHAN WILLIAMS CLASSIFICATION - Class I : sodium inhibitors Ia : Quinidine, Disopyramide Ib : Lidocaïne, Mexiletine Ic : Flecaïnide, Propafenone, Cibenzoline - Class II : beta-blockers - Class III : potassium blockers : Amiodarone, Sotalol - Class IV : calcium inhibitors : Verapamil, Diltiazem

4 EVIDENCE FOR INCREASED MORTALITY IN PATIENTS TREATED WITH ANTIARRHYTHMIC DRUGS Nattel S., et al. Cardiovascular Research 1998

5 Arrhythmias Environment Genetic Susceptibility Bradycardia Gender Hypokalemia Autonomic control Drugs, e.t.c.

6 The concept of Reduced Repolarization reserve Even in susceptible substrate arrhythmias occur very rare and in an unpredictable fashion

7 Proarrhythmia AF Quinidine restored SR Proarrhythmia

8 Brugada Syndrome Reduction in the median number of ICD shocks before and after Quinidine administration The total number of shocks (n= 203) was reduced with quinidine (n=41) Anguera I. et al, JACC 2016

9 Sotalol-Induced QTc prolongation Adapted from Salem et al. PLoS ONE 2017:12(8):e

10 Flutter with 1:1 AV conduction Indian Pacing and Electrophysiology Journal 2010;10(6):

11 Exercise-induced QRS prolongation in a 58-year old patient (physician) who was using propafenone to prevent AF Before ET Recovery (2 min) Αρχείο Γ.Ανδρικόπουλου

12 Arrhythmia & Electrophysiology Review 2016;5(1):45 9

13 Andrikopoulos G. Pastromas S, Tzeis S. World J Cardiol 2015 February 26; 7(2): 76-85

14 The Present Value of Antiarrhythmic Therapy

15 (111. Lafuente-Lafuente C, et al. Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation. Cochrane Database Syst Rev 2007;4:CD005049) European Heart Journal 2010 (doi: /eurheartj/ehq278)

16 Saksena S., et al. JACC 2011 Potential benefit of rhythm control offset by antiarrhythmic drug toxicity

17 Projected Number of People with AF (millions) Projected U.S. Prevalence of AF An Expanding Epidemic Based on Projected Incidence Based on Current Incidence 2 0 Miyakasa Y, et al. Circulation 2006; 114: 119. Year

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19 Leif Frieberg. Safety of Dronedarone in Routine Clinical Care. J Am Coll Cardiol 2014;63:

20 Fifty-Year Trends in Atrial Fibrillation Prevalence, Incidence, Risk Factors, and Mortality in the Community (The Framingham study) During 50 years of observation (202,417 person-years), there were 1,544 new-onset atrial fibrillation cases Lancet July 11; 386(9989) Interpretation Our data suggest that observed trends of increased incidence of atrial fibrillation in the community were partially due to enhanced surveillance. Stroke occurrence and mortality following atrial fibrillation onset declined over the decades, and prevalence increased approximately fourfold. The hazards for atrial fibrillation risk factors remained fairly constant. Our data indicate a need for measures to enhance early detection of atrial fibrillation through increased awareness coupled with targeted screening programs, and risk factor-specific prevention.

21 ESC 2015

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23 What should we do in pts with Enlarged atrial size and Normal WL?

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25 Number of patients SUPRAVENTRICULAR TACHYARRYTHMIAS* IN THE MERLIN - TIMI 36 TRIAL Number of patients A. Supraventricular Tachycardia B. New-Onset Atrial Fibrillation =339, RR 0.81, p<0.001 =20, RR 0.74, p= (53.5%) 75 (2.3%) (43.2%) (1.7%) Placebo Ranolazine 0 Placebo Ranolazine *Detected during 6 days of cecg monitoring Scirica et al. Circulation. 116: , 2007

26 Sudden Cardiac Death RISK OF SUDDEN CARDIAC DEATH ASSOCIATED WITH VENTRICULAR TACHYCARDIA LASTING 8 BEATS Sudden Cardiac Death 8% NO VT VT Patients with No VT 8 beats 8% Patients with VT 8 beats HR 0.96 (95% CI 0.66, 1.42); p=0.85 HR 0.36 (95% CI 0.10, 1.27); p= % 6% Placebo 4% 2% Placebo Ranolazine 4% 2% Ranolazine 0% Days After Randomization Wang W et al. Circulation 120(18): S661, 2562, 2009 Modified from Scirica B et al, Circulation 122:455, % Days After Randomization

27 Types of ionic currents significantly inhibited by therapeutic concentrations of ranolazine in atrial and ventricular cells, and implication of late sodium channel activation in arrhythmogenesis Ηλεκτρική Δυσλειτουργία Αρρυθμίες Μηχανική Δυσλειτουργία Διαστολική Τάση Συσταλτικότητα Προσφορά & Ζήτηση O 2 Κατανάλωση ATP Σχηματισμός ATP Tzeis S, Andrikopoulos G. Antiarrhythmic properties of ranolazine -from bench to bedside. Expert Opin Investig Drugs Aug 23.

28 Scirica B., et al. Europace 2014 Sep 10. pii: euu217. [Epub ahead of print]

29 Methods: This prospective, multicenter, randomized, double-blind, placebo-control parallel group phase II dose-ranging trial randomized patients with persistent AF (7 days-6 months) 2 hours after successful ECV to placebo, ranolazine 375, 500 or 750 mg bid. Patients were monitored daily with transtelephonic ECG. The primary endpoint was the time to first AF recurrence Results: Of 241 patients randomized 238 took at least 1 drug dose. Ranolazine proved to be safe and tolerable. No dose of the drug significantly prolonged time to AF recurrence. AF recurred in 56.4%, 56.9%, 41.7% and 39.7% of the placebo, ranolazine 375 mg, ranolazine 500 mg and ranolazine 750 mg patients, respectively Figure 2: Kaplan- Meier recurrence-free survival curves comparing the mg combined group with placebo (n= 173, A, left) and for the prespecified population of patients who were still in sinus rhythm after 48 hours (n=157, B, right). Heart Rhythm Jan 17. pii: S (15) doi: /j.hrthm [Epub ahead of print]

30 J Cardiovasc Med 2017, 17:

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32 Hard Work or Good luck? Amiodarone Quinidine Ranolazine

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35 Megadata Analysis will boost the development of novel antiarrhythmic strategies