Debate PRO. Dronedarone is an important drug in the management of paroxysmal atrial fibrillation. John Camm

Transcription

1 ESC ICM - Internationales Congress Center München 2012 Atrial Fibrillation Controversies in Medical Treatment Debate Dronedarone is an important drug in the management of paroxysmal atrial fibrillation PRO John Camm St. George s University of London United Kingdom

2 ESC 2012 ICM - Internationales Congress Center München Atrial Fibrillation Controversies in Medical Treatment Debate : Dronedarone is an important drug in the management of paroxysmal atrial fibrillation John Camm Conflicts of Interest: Consultant/Advisor/Speaker Advisor / Speaker : Astra Zeneca, ChanRX, Gilead, Merck, Menarini, Otsuka, Sanofi, Servier, Xention, Bayer, Boehringer Ingleheim, Bristol Myers Squibb, Daiichi, Pfizer, Boston Scientific, Biotronik, Medtronic, St. Jude Medical, Actelion, GlaxoSmithKline, InfoBionic, Incarda, Johnson and Johnson, Mitsubishi, Novartis, Takeda

3 Details of the Motion not the most not LA ablation Dronedarone is an important drug in the management of paroxysmal atrial fibrillation not persistent of permanent

4 AADs for Prevention of AF After DCC Systematic Review of RCTs RCTs included in analysis Total 44 No. of patients 11,322 controlled 25 Active comparator 14 Persistent AF 38 (60% pts) PAF/recent onset 6 EF > 50% 41 Lone AF 1 Follow-up 1 year AF Recurrence Class IA < Class IC < Metoprolol Class III < Amiodarone < Dofetilide < Sotalol < Quinidine vs. class I Quinidine vs. sotalol Amiodarone vs. class I < Amiodarone vs. sotalol < Sotalol vs. class I Lafuente-Lafuente C, et al. Cochrane Database Syst Rev 2007;4:CD Odds ratio (95% CI)

5 AADs for Mortality Reduction after DCC Systematic Review of RCTs Overall Mortality Class IA Class IC Metoprolol Class III Amio Dofetilide Sotalol Q vs Class I Q vs Sotalol Amio vs Class I Amio vs Sotalol Sotalol vs Class I Lafuente-Lafuente C, et al, Arch Intern Med 2006;166: Odds Ratio (95% CI)

6 Dronedarone CH 3 SO 2 NH O O C 4 H 9 (CH 2 ) 3 N C 4 H 9 O C 4 H 9 Amiodarone-like compound lacking iodine Similar electrophysiologic properties No evidence of thyroid or pulmonary toxicity 24-hour half-life Food effect (2 3x increase in plasma levels) Extensive 1 st pass metabolism (CYP450 3A4) 15% bioavailability

7 Cumulative Incidence Cumulative Incidence Dronedarone - Prevention of AF EURIDIS (N=615, follow-up 1 year) ADONIS (N=630, follow-up 1 year) Dronedarone 400 mg bid Time (days) Log-rank test results: p= Time (days) Log-rank test results: p= Singh et al. Presented at: ESC; 2004; Munich, Germany.

8 Cumulative Incidence Cumulative Incidence Symptomatic and Any AF Endpoints EURIDIS Dronedarone 612 pts with AF in SR 1 0 endpoint: 1 st Recurrence of any AF/A Flutter 2 0 endpoint: 1 st Symptomatic AF/AFl Recurrence Episode lasting 10 minutes, i.e. two consecutive ECGs 10 minutes apart TTM with symptoms and on preset intervals Log-rank test results: p= Log-rank test results: p= Time (days) Time (days) Dronedarone 400 mg bid

9 Efficacy of Dronedarone and other AADs including Amiodarone in AF Patients in sinus rhythm at 1 year, % Amiodarone Dronedarone Sotalol Class IC CTAF SAFE-T AFFIRM DAFNE* EURIDIS ADONIS EURIDIS/ADONIS Pooled DIONYSOS** ADONIS = American-Australian-African trial with DronedarONe In atrial fibrillation or flutter for the maintenance of Sinus rhythm; AFFIRM = Atrial Fibrillation Follow up Investigation of Rhythm Management; CTAF = Canadian Trial of Atrial Fibrillation; DAFNE = Dronedarone Atrial FibrillatioN study after Electrical cardioversion; DIONYSOS = Efficacy and Safety of Dronedarone versus Amiodarone for the Maintenance of Sinus Rhythm in Patients with Atrial Fibrillation; EURIDIS = EURopean trial In atrial fibrillation or flutter patients receiving Dronedarone for the maintenance of Sinus rhythm; SAFE-T = Sotalol Amiodarone Atrial Fibrillation Efficacy Trial * At 6 months; ** mean follow-up 7 months Savelieva I, et al. Europace 2011

10 Cumulative incidence Dronedarone Reduces Death and Hospitalisations ADONIS and EURIDIS Pooled Analysis Post hoc N = 1237 Dronedarone: n = 828 : n = 409 ACM + ACHosp Dronedarone vs Estimated event rate at 12 mos (for ACM+All Hosp): 22.8% vs 30.9% Actual event rate at 12 mos (for ACM+CVHosp): 16.1% vs 19.2% (RRR 20%, p = 0.164) Number at risk CVM + CVHosp Dronedarone vs RRR 27% [95% CI, 7% - 43%], p = 0.01 Dronedarone 400 mg bd Days after randomisation Dronedarone Hohnloser SF, AHA 2005, Dallas

11 Cumulative Incidence (%) ATHENA: Primary Outcome Time to first cardiovascular hospitalization or death HR = 0.76 P < Dronedarone Mean follow-up 21 5 months Months Patients at risk Dronedarone Hohnloser SH et al. ATHENA Investigators. N Engl J Med Feb 12;360(7):

12 Cummulative Incidence (%) Cummulative Incidence (%) Total and Cardiovascular Mortality All Cause Mortality (ACM) Not statistically significant Cardiovascular Mortality Analysis plan: not assessed if ACM not +ve HR=0.84 [ ] p= HR=0.71 [ ] p= Dronedarone 2.5 Dronedarone 2 Patients at risk Dronedarone Months Months Mean follow-up 21±5 months Hohnloser SH et al. ATHENA Investigators. N Engl J Med Feb 12;360(7):

13 Cumulative incidence (%) Mean recurrence number Cardiovascular Hospitalization First AF Related All AF Related HR= %CI=[0.55; 0.72] 510 p< HR= %CI=[0.536; 0.730] 829 p< Dronedarone 0.2 Dronedarone Months Months Page R et al, ESC September 2009 post-hoc analysis

14 Was Dronedarone an Effective Antiarrhythmic in ATHENA? Time to 1 st DCV Cumulative incidence, % Time to 1 st AF/AFL Cumulative incidence of AF/AFL, % No. in Permanent AF Number of Patients HR = 0.69 p <0.001 Dronedarone Months HR = 0.75 p <0.001 Dronedarone Months (12.7%) n= 2313 p< (7.7%) n= 2291 Dronedarone on top of standard Rx Page R, et al. AHA Scientific Sessions All AF related hospitalization: HR=0.626, 95% CI = [0.54; 0.73] First AF related hospitalization: HR=0.63, 95% CI = [0.55; 0.72]

15 ATHENA Study Outcomes Outcome RISK REDUCTION P Value CV Hospitalization or Death 1 0 endpoint 24% < Cardiovascular Death 2 0 endpoint 29% Death from Cardiac Arrhythmia 45% 0.01 Cardiovascular Hospitalization 2 0 endpoint 26% < Stroke post-hoc 34% ACS 30% 0.03 All Cause Mortality Not powered 16% 0.176

16 Dronedarone and Proarrhythmia Prolongation of myocardial repolarization and post-repolarization refractoriness by D may act antiarrhythmic. A fast phase 3 repolarization in the absence of both increased dispersion of repolarization and reverse use dependence prevents proarrhythmia.

17 AF Recurrence and All Cause Mortality Odds Ratios compared with Antiarrhythmic Efficacy Dronedarone N= (0.40, 0.72, p=0.0002) Propafenone N= (0.28, 0.48, p<0.0001) Amiodarone N= (0.16, 0.29, p<0.0001) Sotalol N= (0.31, 0.52, p<0.0001) Flecainide N= (0.19, 0.49, p<0.0001) All Cause Mortality Dronedarone N=3378 Amiodarone N=653 Sotalol N= (0.67 to 1.09) p= (1.00 to 7.41) p= (1.59 to 11.70) p=0.013 Freemantle N, et al. Europace 2011;13:

18 Effect of Dronedarone on LV Function 124 patients randomized: Dronedarone 400 mg od Dronedarone 800 mg od Dronedarone 600 mg bid 8 6 Ejection Fraction vs No significant effect Treated for 30 days Primary objectives: Effect of dronedarone on functional capacity Secondary objective: Effects of dronedarone on LVEF mg od 800 mg od 600 mg bd Dronedarone Dose Levine TB, et al. Cardiovasc Drugs Ther. 2010; 24:

19 Reporting rate in patient-years x 1000 Dronedarone 2 year Post-marketing Safety Data Based on the estimated 440,000 patients treated with dronedarone up to 30 June 2011* Reporting rate per 1000 patient-years for serious adverse events per periodic safety update period 1 Jul Jan Feb Jul Aug Jan Feb Jun 2011 *Estimated. IMS/MIDAS Worldwide Monthly Database, Standard Units Sold until 30 June 2011, reported Aug 2011

20 Conclusions Dronedarone is the only AAD developed specifically for use in AF Dronedarone is the only AAD with AF-specific CV outcomes studies Dronedarone is an effective drug for maintenance of sinus rhythm in recurrent AF ATHENA showed conclusively that Dronedarone not only reduced recurrence of AF but also reduced important CV outcome events in a recurrent AF at risk population Dronedarone is an important drug in the management of paroxysmal atrial fibrillation

21 Thank you for your attention