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ANTIARRHYTHMIC DRUGS IN ATRIAL FIBRILLATION: STILL A CHALLENGE ROLE OF CLASS III ANTIARRHYTHMIC DRUGS REVISITED J.Y. LE HEUZEY Georges Pompidou Hospital René Descartes University, Paris Bologna, February 17, 2017 Disclosure Consultant / Conferences / Advisory Board fees from Astra Zeneca, Sanofi, BMS/Pfizer, Meda, Boehringer Ingelheim, Bayer, Novartis, Servier and Daiichi Sankyo. 1- AMIODARONE 9- IBUTILIDE 2- AZIMILIDE 10- NIFEKALANT 3- BRETYLIUM 11- NIFERIDIL 4- BUDIODARONE 12- SEMATILIDE 5- BUNAFTINE 13- SOTALOL 6- CELIVARONE 14- TEDISAMIL 7- DOFETILIDE 15- VERNAKALANT 8- DRONEDARONE 1- AMIODARONE 9- IBUTILIDE 2- AZIMILIDE 10- NIFEKALANT 3- BRETYLIUM 11- NIFERIDIL 4- BUDIODARONE 12- SEMATILIDE 5- BUNAFTINE 13- SOTALOL 6- CELIVARONE 14- TEDISAMIL 7- DOFETILIDE 15- VERNAKALANT 8- DRONEDARONE 1- AMIODARONE 9- IBUTILIDE 2- AZIMILIDE 10- NIFEKALANT 3- BRETYLIUM 11- NIFERIDIL 4- BUDIODARONE 12- SEMATILIDE 5- BUNAFTINE 13- SOTALOL 6- CELIVARONE 14- TEDISAMIL 7- DOFETILIDE 15- VERNAKALANT 8- DRONEDARONE . Pharmacological cardioversion : Amiodarone, Vernakalant . Sinus rhythm maintenance (rhythm control strategy) : Amiodarone, Dronedarone, Sotalol NEW ! Combination Dronedarone + Ranolazine Potassium currents blocked by vernakalant, and potency VERNAKALANT Current IC50 (µM) Ito I 5-30 0 mV to IKur IKur 3-13 IKr IKACh 10 I 7-21 IKACh Kr IKs > 100 0 100 200 300 400 ms IK1 > 100 AAD: Anti-arrhythmic drug IC: Inhibitory concentration Fedida et al. J Card Electrophysiol 2005, p1227-1238 Effect on AERP vs VERP . In an open-label electrophysiologic study in 19 patients, vernakalant significantly prolonged atrial, but not ventricular, effective refractory period – Low-dose vernakalant: 2 mg/kg over 10 min + 0.5 mg/kg/h for 35 min (total dose, ~2.25 mg/kg) – High-dose vernakalant: 4 mg/kg over 10 min + 1 mg/kg/h for 35 min (total dose, ~4.5 mg/kg) Paced cycle length: 600 msec 50 (31 ± 14)a Low Dose 40 High Dose 30 (14 ± 14)a 20 (4 ± 15) (0 ± 10) 10 Change Change From Baseline, msec 0 aP<0.05 vs baseline. AERP VERP AERP=atrial effective refractory period; VERP=ventricular effective refractory period. Dorian P et al. J Cardiovasc Pharmacol. 2007;50:35–40. Adapted with permission from Dorian P et al. J Cardiovasc Pharmacol. 2007. 8 ACT Studies (Phase III) Key Inclusion and Exclusion Criteria Inclusion criteria Exclusion criteria . ACT-I, ACT-III and ACT-IV studies . Female patients pregnant or nursing – Age ≥ 18 years . ECG findings: – Uncorrected QT interval >0.440 – Sustained (> 3 hrs up to 45 days) AF seconds or QRS >0.140 seconds ACT-III included patients with AF – Bradycardia (<50 beats/min) or sick or atrial flutter sinus syndrome, unless controlled by – Hemodynamically stable (systolic a pacemaker BP >90 to <160; diastolic BP <95 mm . Cardiovascular disease: NYHA class IV Hg) heart failure, acute coronary syndrome, myocardial infarction, or cardiac surgery – Adequate anticoagulant therapy within 30 days before enrolment – Weight 45 to 136 kg . Other: – Patients stratified in – Failed direct-current cardioversion Short-duration AF (3 hours to 7 – IV antiarrhythmic therapy within 24 days) (primary endpoint) hrs Long-duration AF (7-45 days) – Reversible cause of AF – Previously failed electric conversion . ACT-II study – Digoxin toxicity – End-stage disease, serious hepatic or – Sustained AF or atrial flutter for 3 to renal disease 72 hours occurring between 24 hours and 7 days after a cardiac – Uncorrected electrolyte imbalance surgery – History of Torsade de Pointes (ACT II) Roy D et al. Circulation. 2008;117:1518-25; Kowey PR et al. Circ Arrhythmia Electrophysiol 2009;2:652-9. ACT Studies (Phase III) Primary Efficacy Endpoint 60% 51.7% 47.0% 51.2% 50.9% 50% Vernakalant 40% Placebo 30% p<0.001 compared to placebo in ACT I, 20% sinus rhythm (%) rhythm sinus 14.0% ACT II, and ACT III 10% Percent conversion of AF to conversion of Percent 4.0% 3.6% 0% ACT I ACT II* ACT III ACT IV *ACT II enrolled patients with AF duration 3-72 hours. Roy D et al. Circulation. 2008;117:1518-25; Kowey PR et al. Circ Arrhythmia Electrophysiol 2009;2:652-9. ACT Studies (Phase III) Other Findings . In those patients who converted to sinus rhythm: – Conversion was successful with the first dose in ~75% – 97.2% of patients remained in sinus rhythm at 24 hours (pooled analysis of ACT I and ACT III studies) . The median time to conversion to sinus rhythm with vernakalant was 11 minutes (pooled analysis of ACT I and ACT III studies) . Vernakalant was not successful in % conversionto sinusrhythm terminating primary atrial flutter Time (minutes) AVRO Study Design R n=116 • Phase 3, multicenter, randomized, double- A blind, active-controlled trial N Vernakalant • Key inclusion criteria: D – Age 18 to 85 years O – Symptomatic AF of 3 to 48 hours M duration I – Eligible for cardioversion Amiodarone Z E n=116 . Primary endpoint: the proportion of patients in SR at 90 minutes after initiating therapy. 12 60 51.7 50 40 30 AVRO 20 10 5.2 0 Vernakalant (N=116) Amiodarone (N=116) Vernakalant (N=116) 0.6 Amiodarone (N=116) Proportion P<0.0001 (Log-rank test) of patients 0.4 Median time to conversion with in vernakalant responders conversion 0.2 was 11 minutes to SR 0.0 0 5 10 20 35 50 70 90 Time (Minutes) AVRO Safety Summary . There were more adverse events in the vernakalant group than the amiodarone group . Most common side effects of vernakalant were dysgeusia (6.9%), sneezing (3.4%) and nausea (2.6%) . One death (pulmonary embolism) in vernakalant group occurred on Day 24 . Cardiac arrest in amiodarone group occurred at 37 minutes after start of first infusion . Ventricular arrhythmia, hypotension and bradycardia were rare and occurred at similar rates between vernakalant and amiodarone groups . There were no cases of TdP or sustained VT . More patients experienced AFL in the vernakalant group (8.6%) than the amiodarone group (0.9%) . There was no 1:1 conduction of AFL . EMA labelling : rapid conversion of recent onset atrial fibrillation to sinus rhythm in adults - for non surgery patients : atrial fibrillation ≤ 7 days duration - for post cardiac surgery patients : atrial fibrillation ≤ 3 days duration. 3 mg/Kg over 10 minute period . Caution +++ in patients with structural heart disease 16 Cardioversion of recent onset of atrial fibrillation Recent onset AF Yes Haemodynamic No instability? ESC 2016 GUIDELINES Elective Patient choice Urgent Pharmacological cardioversion Coronary artery Severe HFrEF, disease, moderate No relevant significant HFrEF or structural aortic stenosis HFmrEF/HFpEF, heart disease abnormal LVH Electrical Intravenous Intravenous Intravenous Pill in the pocket cardioversion (IB) Amiodarone (IA) Vernakalant (IIbB) Flecainide (IA) Flecainide (IIaB) Amiodarone (IA) Ibutilide (IIaB) Propafenone (IIaB) Propafenone (IA) Vernakalant (IA) www.escardio.org/guidelines European Heart Journal - doi:10.1093/eurheartj/ehw 210 BENZOFURANES Amiodarone Budiodarone Celivarone Dronedarone DAFNE 2003 ADONIS 2007 EURIDIS 2007 ERATO 2008 ANDROMEDA 2008 ATHENA 2008 DIONYSOS 2010 PALLAS 2011 Dronedarone Showed a Significant Reduction in First AF Recurrence in Combined Analysis Amiodarone EURIDIS/ADONIS 0.8 Dronedarone 0.7 0.6 25% 0.5 reduction in relative 0.4 risk 0.3 0.2 Hazard ratio, 0.75 (95% CI, 0.65 to 0.87) Cumulative Incidence Cumulative p<0.001 0.1 0 0 60 120 180 240 300 360 Time (days) Placebo + standard therapy Dronedarone 400mg bid + standard therapy Singh BN, et al. N Engl J Med. 2007;357:987-99. 18 Cumulative Incidence of All-cause Mortality 0.8 Placebo Dronedarone 800mg n=317 n=310 0.7 Number of patients who died 12 25 Hazard Ratio 2.13 0.6 95% CI [1.07; 4.25] Log rank p value 0.03 0.5 0.4 Placebo 0.3 DR 400mg bid 0.2 Cumulative Cumulative Incidence 0.1 Time (days) 0.0 0 30 60 90 120 150 180 210 Patients at risk: Placebo 317 256 181 103 50 18 6 1 DR 400mg bid 310 257 174 104 59 22 5 1 Køber L, et al. N Engl J Med. 2008;358:2678-87. 19 Dronedarone Significantly Decreased Risk of CV Hospitalisation or Death by 24% 50 Placebo on top of standard therapy* 24% reduction DR 400mg bid on top of standard therapy* in relative risk 40 30 20 HR=0.76 10 p<0.001 Cumulative (%) Cumulative Incidence 0 Months 0 6 12 18 24 30 Patients at risk: Placebo 2327 1858 1625 1072 385 3 DR 400mg bid 2301 1963 1776 1177 403 2 * Standard therapy may have included rate control agents (beta-blockers, and/or Ca-antagonist and/or digoxin) and/or anti-thrombotic therapy (Vit. K antagonists and /or aspirin and other antiplatelets therapy) and/or other cardiovascular agents such as ACEIs/ARBs and statins. Mean follow-up 21 ±5 months. Hohnloser SH et al. N Engl J Med 2009;360:668-78. 20 DIONYSOS Primary Endpoint: More AF Events But Less Early Discontinuation With Dronedarone 1.0 0.8 184 (73.9%) 43 endpoints 0.6 42 endpoints 141 (55.3%) 0.4 0.2 RRR (95%CI) = 1.589 (1.275;1.98) Cumulative incidence Cumulative p-value <0.001 0.0 0 3 6 9 12 15 Months Dronedarone Patients at risk Amiodarone 249 99 84 40 12 0 255 146 126 61 13 0 Dronedarone Amiodarone (n=249) (n=255) Number of patients with endpoint 184 (73.9%) 141 (55.3%) ECG documented AF endpoint 158 (63.5%) 107 (42.0%) Documented AF after conversion 91 (36.5%) 62 (24.3%) Unsucessful electrical cardioversion 29 (11.6%) 16 (6.3%) No spontaneous conversion and no electrical 38 (15.3%) 29 (11.4%) cardioversion on day 10 to day 28 Premature study drug discontinuation 26 (10.4%) 34 (13.3%) Lack of efficacy 1 (0.4%) 0 Intolerance 25 (10.0%) 34 (13.3%) Le Heuzey J.Y.
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    WTO Documents Online

    WORLD TRADE RESTRICTED G/MA/TAR/RS/291 4 August 2011 ORGANIZATION (11-3946) Committee on Market Access Original: English MODIFICATIONS AND RECTIFICATIONS OF URUGUAY ROUND SCHEDULES Schedule XXXVIII – Japan The following communication, 28 July 2011, is being circulated at the request of the delegation of Japan. _______________ Japan submits herewith the draft modifications and rectifications to Schedule XXXVIII – Japan pursuant to paragraph 3 of the Decision of 26 March 1980 (BISD 27S/25). These modifications and rectifications1 reflect the outcome of the forth review for the coverage of tariff elimination regarding pharmaceutical products and will become effective in accordance with the relevant notification provided by the Government of Japan to the Director-General upon completion of its domestic procedures. _______________ If no objection is notified to the Secretariat within three months from the date of this document, the modifications and rectifications of Schedule XXXVIII – Japan will be deemed approved and formally certified. 1 In English only. MODIFICATIONS AND RECTIFICATIONS TO SCHEDULE XXXVIII – JAPAN G/MA/TAR/RS/291 Page 3 Page 4 G/MA/TAR/RS/291 SCHEDULE XXXVIII – JAPAN PART I MOST-FAVOURED-NATION TARIFF SECTION II Other Products Mark the tariff item number 2843.29, 2910.20, 2921.51 with a letter “P” G/MA/TAR/RS/291 Page 5 Page 6 G/MA/TAR/RS/291 Attachment to SCHEDULE XXXVIII – JAPAN Replace “Annexes IA, IB, IC and ID” in category (3) by “Annexes IA, IB, IC, ID and IE”. Replace “Annex II” in category (4) by “Annexes IIA and IIB. Replace “Annexes IVA, IVB, IVC and IVD” in category (6) by “Annexes IVA, IVB, IVC, IVD and IVE”.