or

Speaker- Dr Sandeep MohananPerceptor- Dr Nishant Verma

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.

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

Trials comparing rate vs rhythm control

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

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

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.

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.

Vaughan Williams Classification• Class 1:1A (Quinidine, Procainamide) - Na (intermediate) & K channel blockers1B (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

The Cardiac Action Potential

VERNAKALANT

• A novel atrial selective antiarrhythmic• Multichannel blocker- IKur, IKACh , INa, Ito, IKr

• Use dependent – The action increases with the rate• Quick offset at the Na channels

IKurIKACh

Selectivity

1) I-Kur2) I- KACh3) 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

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

OBJECTIVE

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

METHODS

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.

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

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

Study interventions• Vernakalant arm : 3mg/kg over 10 mins 15mins

2mg/kg over 10 mins

-60 min infusion of placebo in a 2nd line followed by a same maintainence infusion for another 60 mins

• Amiodarone arm: 5mg/kg over 60 mins

50mg over 60 mins

- Similar Sham-vernakalant infusion separated 15 mins apart.

• 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

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

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 mins3) Change in EQ-5D quality of life VAS from screening to Hour 2

• Exploratory:1) Time to conversion within first 240 mins2) Proportion who met the primary end point with no relapse at 4 hrs3) Proportion who are ready for discharge at 2 hrs

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

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

Disposition of patients

Baseline characteristics

RESULTS

Primary efficacy endpoint

60 out of 116 Vernakalant patients(51.7%) vs6 out of 116 Amiodarone patients ( 5.2%)

( RR-10.0 ; CI 4.5 to 22.2 ; P <0.0001)

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)

At 4 hours post infusion:

54.5% of Vernakalant patients vs22.6 % 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)

Mean Heart rates in the study patients

Safety analysis

1 death – COPD exacerbation and pulmonary embolismSAE – V - Monomorphic UnsustainedVT ( No QT prolongation) , Syncope A - Cardiac arrestOthers - Atrial flutter (10 Vernakalant) , Bradycardia

Effect on the QT interval

CRITICAL APPRAISAL

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.

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

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

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

THANK YOU

Sky is the limit………………..

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

The etiology of AF in India

Causes of AF

EuroQol – EQ-5D VAS

A serious adverse event (SAE) in human drug trials are defined as any untoward medical occurrence that at any dose

• results in death,• is life-threatening• requires inpatient hospitalization or prolongation of existing

hospitalization• results in persistent or significant disability/incapacity,• is a congenital anomaly/birth defect, or• requires intervention to prevent permanent impairment or

damage

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