1. or Dr Sandeep Mohanan Speaker- Dr Sandeep Mohanan Dr Nishant Verma Perceptor- Dr Nishant Verma

2. Epidemiology of AF The m.c arrhythmia in clinical practice Prevalence- 0.4 -1%² ; increases with age Incidence - 9.3/1000 patient-years³ The rate of ischemic stroke among patients with nonvalvular AF averages 5% per year, 2 to 7 times that of people without AF. In patients with rheumatic heart disease and AF in the Framingham Heart Study, stroke risk was increased 17-fold compared with age-matched controls. 2.Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management andstroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285:2370–5. 3. Yasuyuki Iguchi, MD*, Kazumi Kimura, MD, Annual Incidence of Atrial Fibrillation and Related Factorsin Adults. Am J Cardiol 2010;106:1129–1133.

3. Treatment of AF outline Rate control Prevention of thromboembolism Correction of rhythm disturbance Rhythm control: - duration and pattern -severity -underlying cardiovascular disease -age -comorbid conditions

4. Trials comparing rate vs rhythm control

5. Rhythm management in AF Electrical cardioversion: -More efficacy -Needs sedation, unpleasant -Risk of Ventricular arrhythmias Pharmacological - best when < 7days of onset. - less effective in persistent AF

6. Pharmacological rhythm management in AF < 7days ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation. JACC Vol. 48, No. 4, 2006August 15, 2006:e149–246. Flecainide > Propafenone > Dofetilide > Amiodarone > Sotalol

7. Amiodarone Meta-analysis of 18 trials, the efficacy of amiodarone ranged from 34% to 69% with bolus (3 to 7 mg/kg bodyweight) regimens and 55% to 95% when the bolus was followed by a continuous infusion (900 to 3000 mg daily) Predictors of successful conversion were shorter duration of AF, smaller LA size, and higher amiodarone dose. Amiodarone was not superior to other antiarrhythmic drugs for conversion of recent-onset AF but was relatively safe in patients with structural heart disease, including those with LV dysfunction for whom administration of class IC drugs is contraindicated.

8. Problems of antiarrhythmics Risk of TdP and other malignant arrhythmias Less effective in persistent AF Delayed onset of action Significant drug interactions ( Warfarin, Digoxin) The Backgound for a novel atiarrhythmic: The number of drugs available to treat AF is modest, and they have limited efficacy and are associated with a number of adverse effects. We need more effective drugs with optimal safety profiles for rapid conversion of new-onset AF. The number of drugs available to treat AF is modest, and they have limited efficacy and are associated with a number of adverse effects. We need more effective drugs with optimal safety profiles for rapid conversion of new-onset AF.

9. Vaughan Williams Classification Class 1: 1A (Quinidine, Procainamide) - Na (intermediate) & K channel blockers 1B (Lignocaine, Mexiletine ) - Na blockers ( fast ) 1C ( Propafenone, Flecainide) – Na blockers ( slow) Class 2 : Beta blockers Class 3 (Amiodarone, Sotalol, Ibutilide) : K channel blockers Class 4 : Ca channel blockers

10. The Cardiac Action Potential

12. VERNAKALANT A novel atrial selective antiarrhythmic Multichannel blocker -I Kur, I KACh, I Na, I to, I Kr Use dependent Use dependent – The action increases with the rate Quick offset at the Na channels

13. I Kur I KACh Selectivity 1)I-Kur 2)I- KACh 3)I- to 4)I- Na: -Difference in RMPs of atria in comparison to the ventricles; especially at times of incomplete atrial repolarisation Atrial Effective Refractory Period increases, with no significant increases in the ventricular refractory period or conduction

14. Vernakalant hydrochloride: A Novel Atrial-selective agent for the cardioversion of recent-onset atrial fibrillation in the emergency department. Stiell G, Dickinson c et al. Acad Emerg Med. 2010 Nov;17(11):1175-82. Placebo controlled double blind trial Patients with recent-onset AF (> 3 to ≤ 48 hours) 10-minute intravenous infusion of vernakalant or placebo, followed by an additional infusion if necessary. Of 290 patients 59.4% converted to sinus rhythm within 90 minutes compared with 4.9% placebo patients. Median time to conversion with vernakalant was 12 minutes CONCLUSIONS: Vernakalant rapidly converted recent-onset AF to sinus rhythm in over half of patients, was well tolerated, and has the potential to offer an important therapeutic option for rhythm control of recent-onset AF in the ED

15. OBJECTIVE To compare the efficacy and safety of intravenous vernakalant and amiodarone for the acute conversion of recent onset AF.

16. METHODS

17. The study and study population Phase 3, multicenter, randomised, double blind, double dummy, active controlled study Performed in compliance with the guidelines for GCP and the Declaration of Helsinki 254 patients 66 sites in Canada, Australia and Europe.

18. Inclusion criteria Between 18 and 85 yrs Symptomatic recent onset AF ( 3 to 48 hr) Eligible for cardioversion and on adequate anticoagulation as per recommendations Hemodynamically stable

19. Exclusion criteria QT interval > 440 ms Familial long QT syndrome Previous TdP, VF or sustained VT Symptomatic bradycardia or VR< 50/min or AV block QRS > 140 ms Pacemaker Afl Atrial thrombus Unstable CHF, NYHA Class IV MI, Any ACS or cardiac surgery within prior 30days CVA within 3 m Valvular stenosis, HCM, RCM, CP End stage diseases Previously failed electrical cardioversion Digoxin toxicity Any contraindications to amiodarone / Prior exposure to vernakalant

20. Study interventions Vernakalant arm Vernakalant arm : 3mg/kg over 10 mins 15mins 2mg/kg over 10 mins -60 min infusion of placebo in a 2 nd line followed by a same maintainence infusion for another 60 mins

21. Amiodarone arm: Amiodarone arm: 5mg/kg over 60 mins 50mg over 60 mins - Similar Sham-vernakalant infusion separated 15 mins apart.

22. No class I or III agents 24 hr prior to or after infusion No oral/iv amiodarone 90 days/ 30 days predose Monitoring parameters and cut-offs: - QTc >550 ms ; QRS > 180 ms -HR < 40 /min ; Symptomatic bradycardia -SBP <85 mmHg -New BBB -VT, TdP, VF, CHB, Sinus pause > 5 s -Asymptomatic VT ≥ 10 consecutive beats

23. Study population management and endpoint If still in AF – Electrical cardioversion / Rate control 6 hr monitoring before discharge Follow up visit at 7 days Follow up telephone call at 30 days

24. Efficacy analysis Primary: Proportion who have converted to NSR within 90 mins of starting infusion ( for atleast 1min) Secondary: 1) Time to conversion within the first 90 mins after start of infusion. 2) Proportion who have no AF symptoms at 90 mins 3) Change in EQ-5D quality of life VAS from screening to Hour 2 Exploratory: 1) Time to conversion within first 240 mins 2) Proportion who met the primary end point with no relapse at 4 hrs 3) Proportion who are ready for discharge at 2 hrs

25. Safety assessment w/f Adverse events Vital signs 12 lead ECG intervals Continuous telemetry monitoring Continuous 12 lead Holter monitoring - A Ventricular events committee would interpret the rhythms; blinded to treatment allocation

26. Statistical analysis Cochran Mantel-Haenszel test : Comparison of conversion rates Log rank test : Compare time to conversion Fixed effects general linear model : Change EQ- 5D VAS score Repeated measures mixed-effect model : Change of QTc from baseline P value < 0.05 was taken as significant

27. Disposition of patients

28. Baseline characteristics

29. RESULTS

30. Primary efficacy endpoint 60 out of 116 Vernakalant patients(51.7%) vs 6 out of 116 Amiodarone patients ( 5.2%) ( RR-10.0 ; CI 4.5 to 22.2 ; P <0.0001)

31. Secondary & Exploratory endpoints Median time to conversion for Vernakalant was 11 mins ( P < 0.0001) No symptoms at 90 min : 62 / 116 ( 53.4 %) Vernakalant group vs 38/116 ( 32.8%) Amiodarone group ( RR-1.63, 95% CI 1.2 to 2.23; P =0.0012 ) Increase in EQ-5D VAS : 10.9 points vs 5.6 points ( P=0.0006)

32. At 4 hours post infusion: 54.5% of Vernakalant patients vs 22.6 % Amiodarone patients reverted to NSR ( P <0.0001) Sinus rhythm was maintained for 4 hr in 59/60 (98.3 %) of Vernakalant group and 6/6 (100% ) of Amiodarone group. 43/ 116 ( 37.1%) vs 11 / 116 ( 9.5% ) of Vernakalant patients were ready to be discharged at 2hrs. ( P < 0.0001)

33. Mean Heart rates in the study patients

34. Safety analysis 1 death – COPD exacerbation and pulmonary embolism SAE – V - Monomorphic UnsustainedVT ( No QT prolongation), Syncope A - Cardiac arrest Others - Atrial flutter (10 Vernakalant), Bradycardia

35. Effect on the QT interval

36. CRITICAL APPRAISAL

37. DISCUSSION A non-inferiority trial : VERNAKALANT is safe and probably a better alternative to amiodarone. -Lesser risk for recurrence -Less need for long term anticoagulation -Avoidance of lengthy and costly hospital stays Amiodarone dose was comparable to previous studies on efficacy but the short duration and higher patient morbidity might have resulted in lesser efficacy. Martinez-Marcos FJ, Garcia-Garmendia JL, Ortega-Carpio A, Fernandez-Gomez JM, Santos JM, Camacho C. Comparison of intravenous flecainide, propafenone, and amiodarone for conversion of acute atrial fibrillation to sinus rhythm. Am J Cardiol 2000;86:950–3. Khan IA, Mehta NJ, Gowda RM. Amiodarone for pharmacological cardio-version of recent-onset atrial fibrillation. Int J Cardiol 2003;89:239–48.

38. HIGHLIGHTS Double blind RCT Adequate power of study Aptly pointed out the drug’s efficacy in quick cardioversion and early discharge of patients. Older patients Structural heart disease was present in 35% of those enrolled; therefore, it is representative of many patients who are seen with new-onset AF. No drug related deaths

39. LIMITATIONS Short study end points. ? Optimal dosing regimen of amiodarone infusion Background aetiology not mentioned Not taken into consideration the possibility for spontaneous cardioversion. ?Rheumatic heart disease Population had relatively preserved LV function

40. CONCLUSION AND TAKE AWAY THOUGHTS Vernakalant is a novel antiarrhythmic having comparable efficacy and rapid action in the conversion of acute AF; with minimal risks. The need for………… Long term studies with similar efficacy end points. A cost-efficacy analysis of this and other medical cardioversion A study focusing entirely on it with structural heart diseases. Studies in comparison with electrocardioversion of AF, a technique that historically has produced extremely high conversion rates with an excellent record of safety. Role in persistant and long standing AF

41. THANK YOU Sky is the limit………………..

42. Levy S, MaarekM, Coumel P, et al. Characterization of different subsets of atrial fibrillation in general practice in France: the ALFA Study, The College of French Cardiologists. Circulation 1999;99:3028–35 (29).

43. The etiology of AF in India

44. Causes of AF

45. EuroQol – EQ-5D VAS

46. A serious adverse event (SAE) in human drug trials are defined as any untoward medical occurrence that at any doseadverse eventdrug results in death, is life-threateninglife-threatening requires inpatient hospitalization or prolongation of existing hospitalizationhospitalization results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or requires intervention to prevent permanent impairment or damage

47. The dosing of Amiodarone for AF When used to produce cardioversion of AF, amiodarone has been used primarily in IV form (5 mg/kg or 300 mg over 1 h, then 15 to 20 mg/kg for the remaining 23 h). When used in this manner in placebo-controlled or comparative studies, amiodarone has been reported to eventually restore sinus rhythm in 47 to 93% of patients with AF. In most, but not all studies, amiodarone was superior to placebo therapy in producing medical cardioversion. Medical Cardioversion of Atrial Fibrillation.Martin A Alpert MD, FCCP CHEST June 2000 vol. 117 no. 61529-1531