Ibutilide

Zuventus Healthcare Ltd

Ibutilide “The Pure Class III Antiarrhythmic”

Ibutilide Ibutilide is the first 'pure' class III anti-arrhythmic drug to be

available. [1] Approved by the USFDA in Dec.1995 June 2016 (Zuventus Health Care Ltd) received manufacturing &

marketing approval from DCGI India. API as well as finished product developed through “in house R&D” Marketed as “Fibricor”

1. Drugs. 1997 Aug;54(2):312-30.

“Pure Class III”• Ibutilide: “cardiac electrophysiological actions” Only.

• Ibutilide: "Pure" action potential–prolonging drug

• It has no “negative inotropic” effects

Goodman & Gilman's The Pharmacological Basis of Therapeutics - 12th Ed

Amiodarone Dronadarone and sotalol are

mixed acting class-III drugs. Sotalol: Has class II and III activitiesAmiodarone: Has Class I, II, III and IV activities and has multiple cardiac (electrophysiologic characteristics of all 4 classes) & systemic side effects. Dronaderon: Similar to Amiodarone

Ibutilide

Formula: C22H38N2O5S

Chemical Name: Methanesulfonamide, N-{4-{4-(ethylheptylamino)-1- hydroxybutyl}phenyl}, (+)

(-), (E)-2-butenedioate (1:0.5) (hemifumarate salt)

Chemistry

Unique mechanism of action

• Ibutilide, at nanomolar concentrations (10-8), “prolongs repolarization by

activation of a slow, inward current (predominantly sodium).”

• It blocks Potassium channels at 1000 times concentration i.e. (10-5)

• Plasma levels achieved after 1mg infusion are in the range of (10-8)

• This mechanism of action is “unique among available class III drugs”

Naccarelli GV. Am J Cardiol. 1996 Oct 17;78(8A):12-6.

Ibutilide does not have a sodium-blocking, Antiadrenergic, and Calcium blocking activity

Unique Mechanism of Action among available class III drugs

Activation of a late inward sodium current

Increased sodium influx

Shah D. Eur Heart J. 2016 May 21;37(20):1622-5.

Prolongation of the myocardial action potential duration.

+-

V Max

plateau

Slow Na

(Ibutilide)CaNa

NT

QT

APDAction Potential Duration

K+ (other class III)

Repolarization

No Hemodynamic EffectsNo clinically significant Hemodynamic effect (at doses up to

0.03 mg/kg) demonstrated on

– Cardiac output,

– Mean pulmonary arterial pressure

– Capillary wedge pressure

Katherine T. Murray. Ibutilide. Circulation 1998;97;493-497.

Ibutilide: Electrophysiological Effects

No clinically significant effect on QRS (at the recommended dosage)

A dose related prolongation of the QT interval

Prolongation of QT interval is similar in men & women

Prolongs action potential duration and effective refractory periods in both

atria and ventriclesNair M. J Am Board Fam Med. 2011 Jan-Feb;24(1):86-92.

Pharmacokinetics • Ibutilide is intravenously (i.v.)

administered • Due to its high first-pass

metabolism, its not given orally

Katherine T. Murray. Ibutilide. Circulation 1998;97;493-497..http://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/20-491S003.pdf

• The pharmacokinetics of Ibutilide is similar regardless of • The type of atrial arrhythmia, • Age, sex• Left ventricular ejection fraction, • Occurrence of polymorphic

ventricular tachycardia• The concomitant use of digoxin,

CCBs, or β-blockers.

After IV infusion, Ibutilide plasma concentrations rapidly decrease in a multiexponential fashion.

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/20-491S003.pdf

Pharmacokinetics

Indications


For the rapid conversion of

atrial fibrillation or atrial flutter

of recent onset to sinus rhythm.

Ibutilide: Dosage & Administration

Ibutilide infusion should be stopped as soon as the presenting arrhythmia is terminated or in the event of sustained or nonsustained ventricular tachycardia, or marked prolongation of QT or QTc.


Dilution

Solutions used for dilution →

Ibutilide Injection 10 ml one Vial + 50 ml of 5 % Dextrose Injection

Ibutilide Injection 10 ml one Vial + 50 ml of 0.9 % NaCl Injection

Ibutilide Injection may be administered undiluted or diluted in 50 mL of diluent

Admixtures of the product, with approved diluents, are chemically and physically stable for 24 hours at room temperature (15°to 30°C )


Clinical settings for Ibutilide usage(cardioversion in AF and AFL)

1. Recent onset atrial fibrillation or flutter 2. Persistent atrial fibrillation or flutter

a) As standalone therapy b) In patients already on oral amiodarone c) To facilitate electrical cardioversion d) To facilitate cardioversion of atrial flutter by overdrive atrial pacing

3. Post-operative atrial fibrillation or flutter 4. Pre-excited atrial fibrillation in patients with WPW syndrome 5. Atrial fibrillation or flutter during an electrophysiological study

or ablation procedure 6. Children and those with congenital heart disease 7. Elderly patients with atrial fibrillation or flutter

Kartikeya Bhargava. Role of Ibutilide in Atrial Fibrillation Supplement Issue on Atrial Fibrillation . JAPI • August 2016 • Vol. 64.

Contraindications


Patients with history of hypersensitivity to Ibutilide fumarate or excipients in the formulation.

Warnings & Precautions

• Potential to prolong refractoriness When

given with Class Ia and other class III

antiarrhythmic, concomitantly or within 4

hours post infusion

• Class I and III agents may be withheld for at

least 5 half-lives prior to ibutilide infusion

• Potential for Proarrhythmia when given

with drugs that prolong the QT interval, such

as– Phenothiazines,– Tricyclic or Tetracyclic antidepressants– Antihistamines- terfenadine, Astemizole


• Doses of more than two infusions are

not recommended in a single setting

due to the risk of QT prolongation

• Not recommended in

– Patients with QTc intervals > 440

msec.

– Patients with H/O polymorphic

ventricular tachycardias (e.g.,

torsades de pointes).

• More rapid infusion is not recommended.

Side Effects Event Placebo (n=127) Ibutilide (n=586)

n % n %CARDIOVASCULAR Ventricular extrasystoles 1 0.8 30 5.1

Nonsustained monomorphic VT 1 0.8 29 4.9

Nonsustained polymorphic VT — — 16 2.7

Hypotension 2 1.6 12 2.0

Bundle branch block — — 11 1.9

Sustained polymorphic VT — — 10 1.7

AV block 1 0.8 9 1.5

Hypertension — — 7 1.2

QT segment prolonged — — 7 1.2

Bradycardia 1 0.8 7 1.2

Palpitation 1 0.8 6 1.0

Tachycardia 1 0.8 16 2.7

GASTROINTESTINAL Nausea 1 0.8 11 1.9

CENTRAL NERVOUS SYSTEM

Headache 4 3.1 21 3.6

Common Non-arrhythmic Toxicity of most frequently used anti-arrhythmic agents in

AF/AFL Ibutilide Nausea

Amiodarone Tremor, peripheral neuropathy, pulmonary inflammation, hypothyroidism and hyperthyroidism, photosensitivity

Dofetilide Nausea

Propafenone Taste disturbance, dyspepsia, nausea, vomiting

Flecainide Dizziness, nausea, headache, decreased myocardial contractility

Sotalol Hypotension, bronchospasm

Harrison's Principles of Internal Medicine, 18th Ed. Chapter 233. The Tachyarrhythmias >

Pro-arrhythmic Manifestations

Amiodarone

Sinus bradycardia, AV block, increase in defibrillation threshold

Rare: long QT and torsades des pointes, 1:1 ventricular conduction with atrial flutter

Ibutilide Long QT and torsades de pointes

Flecainide 1:1 Ventricular response to atrial flutter; increased risk of some ventricular tachycardias in patients with structural heart disease; sinus bradycardia

Dofetilide Long QT and torsades des pointes

Propafenone 1:1 Ventricular response to atrial flutter; increased risk of some ventricular tachycardias in patients with structural heart disease; sinus bradycardia

Sotalol Long QT and torsades des pointes, sinus bradycardia

Harrison's Principles of Internal Medicine, 18th Ed. Chapter 233. The Tachyarrhythmias

How to reduce Torsades de pointes Pretreatment with Class IC drugs

Class IC drugs: Flecainide and Propafenone.• Ibutilide effect is mediated through the delay of slow Na(+) current

inactivation.1

• Pretreatment with IC agents can reduce the increase in QTc seen with Ibutilide2

• There is lower risk of Proarrhythmia since the class IC drugs induced slow conduction by blocking sodium channels which exert somewhat protective effect against Ibutilide toxicity.

• Ibutilide has been safely used in patients who are already on class IC drugs.

1. Kartikeya Bhargava. Supplement Issue on Atrial Fibrillation . JAPI • August 2016 • Vol. 64. 2. Reiffel JA. J Cardiovasc Pharmacol Ther. 2000 Jul;5(3):177-81.

• Combined therapy of iv esmolol and Ibutilide vs.

Ibutilide alone in patients with recent onset AF showed

a higher rate of conversion to sinus rhythm (67% vs.

46%), reduced rate of immediate recurrence and a

lower risk of proarrhythmia1

• The addition of Esmolol reduces QTc prolongation and

diminishes the risk of ventricular tachycardia

• Magnesium prevents significant prolongation of QT interval

and therefore reduces the risks of torsade de pointes2

1. Fragakis N. Europace 2009; 11:70. 2. Wang A. Pharm Pract (Granada). 2012 Apr;10(2):65-71. 21

How to reduce Torsades de pointesIbutilide in combination with Esmolol or MgSO4

Predictor of successful cardioversion with Ibutilide

1. Recent onset of arrhythmia

2. Atrial flutter rhythm

3. Relatively high heart rate

4. Lack of a H/O of CHF

5. Lack of concomitant digoxin therapy

6. Female gender and younger age

Zaqqa M. Am J Cardiol. 2000 Jan 1;85(1):112-4, A9.

Geriatric Use

• Usually start at the low end of the dosing

range, because of

– Decreased hepatic or renal function

– Decreased Cardiac function

– Concomitant disease or other drug therapy.


• Clinical experience shows no difference in responses

between the elderly & younger patients.

Use in Patients with Hepatic or Renal Dysfunction

• The safety, effectiveness & pharmacokinetics

of Ibutilide have not been established in

patients with hepatic or renal dysfunction.

• It is unlikely that dosing adjustments would be

necessary in patients with compromised renal

or hepatic function

• Patients with abnormal liver function should be

monitored for >4-hour period.


Recommendations

Recommendation from AHA/ACC/HRS Guidelines 2014

Anti-arrhythmic Drugs

Class of Recommendation in following Indications

Atrial Fibrillation/Flutter

Wolff Parkinson White and

Pre-excitation Syndrome

Post operative Cardiac &

Thoracic Surgery induced AF

Ibutilide Class I Class I Class IIa

Amiodarone Class IIa Not recommended Not recommended

Flecainide Class I (in Hospital)Class IIa (outside hospital with β-blocker)

Not recommended Not recommended

Dofetilide Class I Not recommended Not recommended

Propafenone Class I (in Hospital)Class IIa (outside hospital with β-blocker)

Not recommended Not recommended

Class-I Recommendation:Benefit >>> Risk ;Procedure/treatment SHOULD be performed/administeredClass-II Recommendation: CLASS II a - Benefit >> Risk Additional studies with focused objectives needed ; IT IS REASONABLE to perform procedure/administer treatment; CLASS II b -Benefit ≥ Risk ;Additional studies with broad objectives needed; additional registry data would be helpful Procedure/treatment MAY BE CONSIDERED

Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol.2014;64(21):2246-2280.

28

Ibutilide Use In Different Clinical Settings

IBUTILIDE Rescue for failed Amiodarone therapy

SN

Title N Drugs Primary Endpoint Results

1 Marcus G. Hennersdorf et al. Conversion of recent onset atrial fibrillation or flutter with ibutilide after amiodarone has failed. Intensive Care Med. 2002 Jul;28(7):925-9.

26 Ibutilide (1 mg or, 2 mg i.v.) after Amiodarone (150 mg i.v.) failed in Persistent arrhythmia

Conversion of recent onset atrialfibrillation or flutter after amiodarone has failed.

Ibutilide led “Sinus Rhythm” conversion in 81.5% of patients where Amiodarone had failed

29

• 70 pts on longterm oral amiodarone for cardioversion in “Afib” (57/70) or “Afl” (13/70)

• Patients administered 2 mg i.v. Ibutilide. • 55 patients (79%) had structural heart disease.

• Patients on amiodarone:153 days• Patients with arrhythmia for 196 days before cardioversion.

Kathy Glatter. Circulation. 2001;103:253-257.

Patients converted within 30 minutes of infusion. AFib- 22 of 57 (39%) and AFl -7 of 13 (54%)only 1 episode of torsade de pointes occurred

Ibutilide Add-on to long term Oral Amiodarone

30

Ibutilide Vs. Amiodarone (i.v.) in AF & AFl N= 152 (Ibutilide n=79, Amiodarone n= 73) Duration of AF or Afl: 3-48 h

Conversion to SR

All patientsIbutilide: 63 of 79 pts (80%) Amiodarone: 42 of 73 pts (57%)

In AFLIbutilide: 20 of 23 pts (87%) Amiodarone: 6 of 21 pts (29%) In AFIbutilide:43 of 56 pts (77%)Amiodarone: 36 of 52 pts (69%)

80%

57%

77%

69%

87%

29%

Ibutilide is more effective than amiodarone in converting recent-onset AF or AFl to Sinus Rhythm

Kafkas NV. Int J Cardiol. 2007 Jun 12;118(3):321-5. 31

Ibutilide: Shorter Arrhythmia Termination Time

Kafkas NV, Int J Cardiol. 2007 Jun 12;118(3):321-5.

Atrial Fibrillation

53.4 min

492 min

Atrial Flutter

28.4 min

762 min

32

Ibutilide vs. Propafenone

SN Title N Drugs Primary Endpoint

Results

1 Zhang HC et al. Immediate cardioversion of atrial fibrillation and atrial flutter lasting less than 90 days by ibutilide versus propafenone: a multicentre study. Zhonghua Yi Xue Za Zhi. 2005 Mar 30;85(12):798-801.

212 Ibutilide (1 mg) (n = 107), 75 AF & 32 AFL

Propafenone (70 mg)

(n = 105, 76 AF & 29 AFL IV over 10 mins

Cardioversion AFL conversion rate Ibutilide = 78.1% Propafenone 48.3%

33

Ibutilide vs. Propafenone Ibutilide 1 mg or Propafenone 70 mg [2 infusions, 10 min apart] N= 82 pts with AF Onset : 2 h to 90 days The treatment was considered successful if sinus rhythm occurred within 90 mins

p = 0.043

Zhang N. Int J Clin Pract. 2005 Dec;59(12):1395-400. Ibutilide is more effective than intravenous propafenone for the cardioversion

34

Sun JL. Cardiovasc Drugs Ther. 2005 Jan;19(1):57-64.

Ibutilide was superior to propafenone for treating atrial flutter (90% vs. 30%).

n=40Ibutilide-20Propafenone-20

Bradycardia & hypotension were more common side effects with propafenone.

Randomized to receive Ibutilide 1 mg Propafenone 70mg

Ibutilide vs. Propafenone

35

Ibutilide with Propafenone3 John A. Chiladaki et al.

Ibutilide added to propafenone for the conversion of atrial fibrillation and atrial flutter. J Am Coll Cardiol. 2004 Aug 18;44(4):859-63.

202 Oral propafenone N=202With AF/AFL without left ventricular dysfunction.IV Ibutilide (1mg) N=104 (48 pts with paroxysmal arrhythmia, & 56 with chronic arrhythmia)

Safety & efficacy of Ibutilide when added to propafenone

Ibutilide offered an overall conversion efficacy of 66.3%.

• 70.8% for patients with paroxysmal AF/AFL

• 62.5% for patients with chronic AF/AFL.

36

Ibutilide 2mgCardioversion of pts on Class IC Agents

• Total 71 pts. AF (n=48) & AFL (n= 23)• Pts. on Propafenone 300 to 900 mg/day (n=46) or Flecainide 100 to 300

mg/day (n= 25)

Conversion rates:

AF - 23 of 48 pts (47.9%)

AFL- 17 of 23 pts (73.9%)

No pts needed to stop of Ibutilide infusion

for ventricular dysrhythmia or excessive

QT prolongation.

Attenuation of Ibutilide-induced QTC prolongation: Class IC agents block slow inward INa in addition to fast INa

In this study mean Ibutilide-induced QTC interval prolongation was 20

ms as compared to 47 to 90ms (reported in literature) This attenuation is without decrease in Ibutilide efficacy

Hongo RH. J Am Coll Cardiol. 2004 Aug 18;44(4):864-8.37

Ibutilide Vs. Procainamide

ADVERSE EVENTS : More common with procainamide (46.2%) than with Ibutilide group -29.0% Ibutilide - Extrasystole occurred .Procainamide - Headache, hypotension, flushing, dizziness and hypesthesia

Volgman AS. J Am Coll Cardiol. 1998 May;31(6):1414-9.

Combined Conversion rates Ibutilide –58%Procainamide - 18%

Atrial Flutter Ibutilide -76% Procainamide -14%

Atrial Fibrillation Ibutilide - 51% Procainamide -21%

Study Establishes The Superior Efficacy Of Ibutilide Over ProcainamideTotal N= 120 , Ibutilide n=60 procainamide n=60

38

Randomized, double-blinded comparative study- 136 patients treated :• i.v. Ibutilide (n=73) • placebo (n=22) • iv procainamide (n=53)

Bruce S. Stambler et al. Circulation. 1997;96:4298-4306

Ibutilide Vs. Procainamide

In AFLIbutilide converted 29 of 45 pts= 64% Procainamide & placebo converted 0% In AFIbutilide converted 9 of 28 pts 32% Procainamide converted in 1 of 20 5% Placebo converted 0%

39

Ibutilide vs. Procainamide

SN

Title N Drugs Primary Endpoint

Results

3 Stambler BS et al.; Comparative efficacy of iv Ibutilide versus procainamide for enhancing termination of atrial flutter by atrial overdrive pacing Am J Cardiol. 1996 May 1;77(11):960-6.

54 Ibutilide n=15 orProcainamide n=33 orPlacebo n =11

Termination of atrial flutter

Pacing converted SR18% placebo, 87% ibutilide, (88%) procainamide

40

Ibutilide vs. Sotalol

Vos M. et al. Heart. 1998;79(6):568-575.]

• Ibutilide (given in 1 or 2 mg doses over 10 mins Rapidly terminates persistent AF or AFL.

• Ibutilide (2 mg) was superior to Sotalol in both atrial flutter and fibrillation• Ibutilide vs Sotalol in Atrial flutter (70% vs. 19%), • Ibutilide vs Sotalol in Atrial Fibrillation (44% v 11%)

Double blind, randomised study.

308 patients with atrial fibrillation (n = 251) or atrial flutter (n = 57) (duration 3 hrs to 45 days) .three groups :1 mg ibutilide (n = 99)2 mg ibutilide (n = 106)1.5 mg/kg DL-sotalol (n = 103)

41

Magnesium as an adjunct to Ibutilide, improves efficacy & minimize toxicity

1. Magnesium have intrinsic

antiarrhythmic properties

2. Potential to increase the

efficacy of class III

antiarrhythmics

3. Delays AV node

conduction, without

significant effect on the

sinus node

3. Efficacy of magnesium &

Ibutilide combination is

due to the additive

potassium blockade effect

4. Side effects of magnesium

are usually mild : e.g. minor

tingling, flushing & dizziness

Wang A. Pharm Pract (Granada). 2012 Apr;10(2):65-71.

42

Magnesium as an adjunct for Ibutilide…..

• Therefore, magnesium with Ibutilide involves

minimal risks with monitoring of vital signs &

ECG.

• Magnesium prevents significant prolongation

of QT interval and therefore reduces the risks

of torsade de pointes

The administration of magnesium makes Ibutilide a much safer

agent, & magnesium increased the conversion efficacy of IbutilideWang A. Pharm Pract (Granada). 2012 Apr;10(2):65-71.

4 g of magnesium may be given within 2 hrs prior to initiation of

Ibutilide for conversion of AF or typical flutter

43

Ibutilide and Magnesium Combination Therapy

Article Study Design Groups Doses of magnesium used

Rates of Successful Cardioversion

Kalus JS. Am J Health Syst Pharm. 2003 Nov 15;60(22):2308-12.

Retrospective, cohortN = 321

1. Control: Ibutilide alone N = 214

2. Treatment: Ibutilide & MgSO4

N = 107

Mean total dose: 2.2 + 1 grams Magnesium was

given within 2 hours before or during ibutilide

therapy

Treatment group: 72%

Control group: 60.3%

p = 0.04

Patsilinakos S. Am J Cardiol. 2010 Sep 1;106(5):673-6.

Prospective

N = 476

1) Ibutilide alone N = 2292] Ibutilide & MgSO4

N = 247

5 grams given 1 hour prior to first dose of Ibutilide, followed by another 5 grams given over 2 hours

Treatment group: 76.5% Control group: 67.3% p = 0.033

Steinwender C. Int J Cardiol. 2010 Jun 11;141(3):260-5.

Randomized, placebo controlled N = 117

1. Ibutilide and placebo

N = 592. Ibutilide & MgSO4 N = 58

Magnesium 4 grams or placebo given 20 minutes prior to first dose of ibutilide

Treatment group (typical AF): 85% Control group (typical AF): 59% p = 0.017

Tercius AJ. Pacing Clin Electrophysiol 2007 Nov;30(11):1331-5.

Retrospective cohort N = 229

1. Ibutilide only N = 88 2. Ibutilide & MgSO4

N = 141

Magnesium 1-4 grams within 2 hours prior to ibutilide

78% more chances of conversion with combination versus 59.8% without MgSO444

1

Stavros E. Et al. Ibutilide to expedite ED therapy for recent-onset atrial fibrillation flutter Am J Emerg Med.2006 Jul;24(4):407-12.

Total = 36 (AFib = 26) & (AFl = 10)

Ibutilide 1 mgSuccessfulconversion within 1 hour

90% patients with AFl and 61.5% patients with AFib converted to sinus rhythm No significant complications occurred.

2

Amy Eversole.et al. Ibutilide: Efficacy and Safety in Atrial Fibrillation and Atrial Flutter in a General Cardiology Practice. Clin. Cardiol. 2001;24,521-525

Total = 54Afib (n=34)Afl (n= 20)

Ibutilide1 mg for pts ≥ 60 kg & 0.1 mg/kg for pts < 60 kg

Successful cardioversion

70.6% pts with AFib & 75% with AFl converted to SR. Conversion of AFib to SR more likely if duration of AFib = 96 h versus >96 h (81 % vs. 17%).

3

Gowda RM.et al. Use of ibutilide for cardioversion of recent-onset atrial fibrillation and flutter in elderly. Am J Ther. 2004 Mar-Apr;11(2):95-7.

Total = 32AFib n=19AFl n =13

Ibutilide 1 mg Cardioversion

Successful Arrhythmia Termination = 59%.63% in patients with AFib & 54% in AFlThe mean conversion time was 33 +/- 45 minutes.

Efficacy of Ibutilide

45

44 patients (75%) converted to SR after Ibutilide 31 on single dose (53%) & 13 on double dose (22%)

Ibutilide in AFL- Single vs Double Dose

Andò G. Minerva Cardioangiol. 2004 Feb;52(1):37-42.

The mean time to the 2nd dose was 34 min in responders

46

N= 59 patients dose- 1 mg Ibutilide.

• 266 pts with AF (n = 133) or flutter (n = 133), • Arrhythmia duration - 3 hrs to 45 days• Randomized to receive up to two 10-min infusions of

– Ibutilide (1.0 and 0.5 mg) or– Ibutilide (1.0 and 1.0 mg)– Placebo

• The conversion rate – 47% after Ibutilide &– 2% after placebo

• Efficacy was higher in AFl than fibrillation (63% versus 31%)• Arrhythmia termination - 27 min after start of the infusion• Of 180 Ibutilide-treated patients, 15 (8.3%) developed polymorphic ventricular

tachycardia during or soon after the infusion

Efficacy and safety of Repeated I.V. doses of Ibutilide

Ibutilide given in repeated doses is effective in rapidly terminating AF & AFl

Stambler B et al. Circulation 1996;94:1613-1621. 47

Ibutilide Vs. Placebo

SN Title N Drugs Primary

Endpoints Results & conclusion

1

Abi-Mansour P.et al. Am Heart J. 1998 Oct;136(4 Pt 1):632-42.

n=250 Ibutilide 1 mg(n=209)

or Placebo(n=41)

Termination of atrial fibrillation or flutter

34.9% of ibutilide Pts had cardioversion within 1.5 hrs0% of placebo PtsAt 24 Hrs, 86.3% of Ibutilide recipients remained in SR

2

James T. VanderLugt.et al. Efficacy and Safety of Ibutilide Fumarate for the Conversion of Atrial Arrhythmias After Cardiac Surgery. Circulation. 1999;100: 369-375.

n = 302AFib=20

1 AFl=101

Ibutilide (n= 218)(0.25, 0.5, or 1.0 mg)

or Placebo (n=84)

Conversion within 90 mins

Conversion rates = Placebo 15%; Ibutilide 0.25 mg 40%, 0.5 mg 47%, and 1.0 mg 57%Mean time to conversion decreased as the Ibutilide dose was increased

48

Ibutilide in different conditions & procedures

Pretreatment with Ibutilide facilitate Electrical cardioversion

• It increases the conversion rate1

• Reduces the energy required to cardiovert2

• Reduces the number of attempts at cardioversion1 • Successful cardioversion in patients who failed initial

shock without Ibutilide pretreatment1 • 100% with Ibutilide versus 72 % without Ibutilide

1. Oral H. N Engl J Med 1999; 340:1849–54.2. Mazzocca G. J Cardiovasc Med 2006; 7:124–8.

Ibutilide 1 mg with electrical cardioversion

51

n =100Transthoracic cardioversion

with or without pre-treatment

Pretreatment reduced mean energy required for defibrillation (166 J vs. 228 J without pretreatment)

Oral H. N Engl J Med. 1999 Jun 17;340(24):1849-54.

Ibutilide for conversion after Cardiac Surgery

Ibutilide: Higher conversion rates than placebo, efficacy was dose related Polymorphic ventricular tachycardia - in Ibutilide group 1.8% vs. 1.2% in placebo group

N= 302, Fibrillation- 201, flutter- 101

Ibutilide is a safe treatment alternative for Post cardiac surgery Atrial Arrhythmias

VanderLugt JT. Circulation. 1999 Jul 27;100(4):369-75.52

Ibutilide in children & patients with Congenital Heart Disease

RESULTS:– 74 episodes of AFl and 4 episodes of AF

(median episodes / patient was 1, range 1-31).

– Ibutilide converted 55 of all the episodes (71%).

– Success during its first-ever administration in 12 of 19 patients: 63%.

– One patient went into torsade de pointes.

Hoyer AW. Pacing Clin Electrophysiol. 2007 Aug;30(8):1003-8.

19 patients (age 6 mths to 34 years) who received Ibutilide between 1996-2005 15 patients with CHD (14 had prior heart surgery); 4 children had normal heart structure.

Ibutilide - effective in selected paedo pts for cardioversion of AFL

53

• Ibutilide successfully terminated AF in 95% of

patients (including children) during

electrophysiology study of accessory pathways

that were subsequently ablated. 1

• Ibutilide an alternative to Procainamide for

cardioversion in stable pts with preexcited AF.2

Ibutilide in Preexcited AF in WPW Syndrome

1. Glatter KA. Circulation. 2001 Oct 16;104(16):1933-9. 2. Varriale P. Pacing Clin Electrophysiol. 1999 Aug;22(8):1267-9.

54

Ibutilide Enhances Termination of AFl by Burst Atrial Overdrive Pacing

• 26 patients for “pacing termination” with standard protocol of “Burst Atrial Overdrive Pacing”

• Ibutilide enhanced pacing-induced termination of AFl compared to placebo (p <0.001) .

• PACING CONVERSION:– 2 of 11 patients (18%) on placebo– 13 of 15 patients (87%) on Ibutilide.

Stambler BS. Am J Cardiol. 1996 May 1;77(11):960-6. 55

n=87 (AFL duration 2 hr to 30 days)randomized :Group 1—i.v. Ibutilide treatment, up to 2 mgGroup 2—ATP with “burst” and “ramp” pacing protocols

Andrea Mazza et al. Europace 2004;6:301-30656

Ibutilide vs. Transoesophageal Atrial Pacing

Andrea Mazza et al. Europace 2004;6:301-306

Group 1: i.v. ibutilide

Group 2: Transoesophageal atrial pacing

Rate of sinus rhythm restoration

Ibutilide appears to be the best choice in AFL

Ibutilide vs. Transoesophageal Atrial Pacing

Ibutilide after Radiofrequency Ablation

58

Ibutilide after Radiofrequency AblationSN Title N

Drugs Primary Endpoints Results & conclusion

1

Tian XC.et al. Efficacy of ibutilide for cardioversion of persistent Afib during radiofrequency ablation. Zhonghua Xin Xue Guan Bing Za Zhi. 2011 Nov; 39(11):1029-32.

AFib(n = 18)

Pts treated with 1 mg Ibutilide within 10 minutes after unsuccessful ablation

Cardioversion Ibutilide is highly effective and safe for cardioversion in pts where ablation failed. After Ibutilide administration 61.11% converted to SR. The average conversion time was 13.80 min.

2

Hou Yu.et al. Single dose of ibutilide for conversion of persistent Atrial fibrillation after radiofrequency ablation. Chin Med J (Engl). 2011 Mar;124(5):710-713

AFib (n = 40)

Pts whose AFib was not converted to sinus rhythm after radiofrequency ablation were given 1mg Ibutilide.

Rate of conversion

Ibutilide converted 72.5% patients to sinus rhythm.Mean conversion time = 13 mins.No cases of serious arrhythmias or other adverse reactions were found.

59

The Modified Ablation Guided by Ibutilide Use in Chronic Atrial Fibrillation (MAGIC-AF) Study

• International multicenter RCT

• Assessed the utility of the intraprocedural

administration of 0.25 mg of

iv Ibutilide before performing Complex

fractionated atrial electrograms (CFAE)

ablation

Singh SM. Eur Heart J. 2016 May 21;37(20):1614-21.

200 pts undergoing a first-ever persistent AF catheter ablation procedure

were randomly assigned to receive either

0.25 mg of iv Ibutilide or

saline placebo

CFAE sites were then targeted with ablation. 60

MAGIC-AF Study continued……

When CFAE ablation was guided by Ibutilide

administration it results into

– Reduction in CFAE area and

– Greater AF termination (75 vs. 57%)

Singh SM. Eur Heart J. 2016 May 21;37(20):1614-21. 61

Ibutilide for AF and flutter in cancer pts.

RESULTS:• Successful cardioversion in 75% of

patients • 68 patients (84%) were on at least 1

medication that prolonged the QT interval at the time of Ibutilide administration

• No significant changes in the corrected QT interval post Ibutilide cardioversion

Bickford CL. Am J Med Sci. 2014 Apr;347(4):277-81.

Centre: University of Texas MD Anderson Cancer Center 81 patients received Ibutilide for AF/AFL from January 2002 to May 2006

Ibutilide is safe and effective in cancer pts.Despite the use of multiple drugs that can potentially prolong the QT interval, no patient experienced serious rhythm disturbances or significant QT prolongation during Ibutilide administration

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Ibutilide in CAD (Coronary Artery Disease)

MVD (Mitral Valve Disease) and LAH (Left Atrial Hypertrophy)

The response rate in patients with CAD was higher than in patients without CAD (23/30= 77%, vs. 33/71= 46%)

Das MK. Clin Cardiol. 2002 Sep;25(9):411-5.

n=101

63

Continued……..

Ibutilide success rate:Presence of MVD- 37.7% (23/61 pts)Absence of MVD- 82.5% (33/40 pts) (p <0.01)

Ibutilide Response rate: 85% (29 of 34 ) in pts without MVD & without markedly enlarged LA

Ibutilide is most effective in patients with CAD or in patients without MVD and/or without markedly enlarged LA

Das MK. Clin Cardiol. 2002 Sep;25(9):411-5.64

Fibricor Summary1. Ibutilide is Pure class III antiarrhythmic drug for AFL and AF2. Quick onset of action (with in minutes)3. Best in class III antiarrythmics4. Easy and rapid administration5. Low incidence of adverse effects6. A good alternative to electrical cardioversion7. Ibutilide Pretreatment increases electrical conversion from 72% to 100%8. Can be used safely in AF/ AFL patients receiving oral amiodarone9. Accessory pathway-mediated AF- the conversion rate of Ibutilide is 95%. 10.Safe and effective in post-cardiac surgery AF patients11.Risk of torsades de pointes (TDP)- up to 4% 12.Proarrhythmia prevented by Class IC drugs (Flecainide & Propafenone)

or IV Esmolol or Mg SO413.Monitor at least for 4 hrs or until QTc has returned to baseline14.The anticoagulation strategy is the same as for any other mode of

cardioversion

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Health & Medicine

Ibutilide