Pharmacologic_Treatment_of_AFib

Pharmacologic Treatment of AFib

Antiarrhythmic Drug

Pros: Maintain normal sinus rhythm/ectopy symptoms Improve hemodynamics stroke/peripheral embolic risk (??)

Cons: Nuisance side effects Organ toxicity Proarrhythmia Other cardiotoxicity Uncertain—persistent need for

anticoagulation, rate control

?? = still theoretical.

Rate Control/Anticoagulate

Pros: symptoms due to increased

heart rate stroke/peripheral embolic risk No serious toxicity/proarrhythmia Low cost Possible once-a-day dosing

Cons: bleeding risk Loss of atrial transport

Antiarrhythmic Agents Approved for the Treatment of AFib

IVEsmolol (Brevibloc): class IIDiltiazem (Cardizem): class IVPropranolol (Inderal): class IIDigoxin (Lanoxin)

IV

Ibutilide (Corvert ) class III

Quinidine gluconate: class IA

Oral

Verapamil (Calan, Isoptin, etc.: class IV

Propranolol (Inderal): class II

Digoxin (Lanoxin)

Oral

Sotalol (BETAPACE AF): class III

Quinidine (Quinaglute), etc.: class IA

Propafenone (Rythmol): class IC

Flecainide (Tambocor ): class IC

Dofetilide (Tikosyn): class III

Rate Control Sinus Rhythm

Drugs Not Approved for Atrial Fibrillation

Amiodarone (eg, Cordarone®) class III

Procainamide (eg, Procanbid®) class IA

Disopyramide (eg, Norpace®) class IA

Moricizine (eg, Ethmozine®) class I

Other sotalol formulations class III

Antiarrhythmic Drug Algorithm to Prevent AFib

CAD=coronary artery disease; CHF=congestive heart failure; HBP=high blood pressure.Prystowsky EN. Am J Cardiol. 2000;85(10A):3D-11D.*BETAPACE AF™: The only sotalol formulation FDA-approved for treatment of AFib/AFL.

Sotalol* Disopyramide CR

Amiodarone

Disopyramide CRDofetilide

AmiodaroneQuinidine

FlecainideSotalol*

Lone AFibHeart Disease

Propafenone

Disopyramide CRPropafenoneAmiodarone

AmiodaroneDofetilide

CAD

Sotalol*

HBP

Initial

Secondary

CHF

Initial Initial

Secondary

Initial

Secondary

BETAPACE AF™ Y Y Y Y Y Y Y N

Betapace® N N N N N N N Y

Generic sotalol N N N N N N N Y

Issues of enhanced patientsafety with BETAPACE AF

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Avoidable adverse events due to inappropriate dosing or inadequate patient education and support

Atrial Fibrillation

Established

Persistent (Requires cardioversion)Persistent (Requires cardioversion)

Permanent (NSR is not/cannot be restored)Permanent (NSR is not/cannot be restored)

Paroxysmal-(Self-terminating)Paroxysmal-(Self-terminating)

Drug Algorithm for Rate Control in AFib1

BB=beta-blocker; BTS=brady-tachy syndrome; CAD=coronary artery disease; CCB=calcium channel blocker; CHF=congestive heart failure; COPD=chronic obstructive pulmonary disease; HTN=hypertension; PVD=peripheral vascular disease. *Varies with ischemic and ventricular functional status and infarct type.

Reference: 1. Reiffel JA, Camm AJ, Haffajee CI, et al. CME Report. International Consensus Roundtable on Atrial Fibrillation. Cardiology Review. 2000;17(suppl):1-20

HTN

CCBBB

Digoxin

CHF

DigoxinBB

CAD

BB

Digoxin/CCB*

BTS

Pindolol

Pacer &alternativedrug

COPD

Verapamil

DiltiazemDigoxin

PVD

CCB

Digoxin

Lone AFib

CCBBB

Digoxin

1st-ChoiceAgents:

2nd-ChoiceAgents:

(Based on Efficacy, Tolerance, and Disease Interactions)

AFib: Benefits of Normal SinusRhythm Maintenance

Relieves symptoms

Improves ventricular performance/exercise capacity

Prevents progression or later development of symptoms

Possibly reduces need for an anticoagulant

Fuster V et al. J Am Coll Cardiol. 2001;38:1231-1265.

1. Reiffel JA. Am J Cardiol. 2000;85(10A):12D-19D.

Goals of Antiarrhythmic DrugTherapy for the Treatment of AFib1

Accomplish pharmacologic cardioversion

Facilitate DC cardioversion (class III)

Maintain NSR to allow reversal of atrial remodeling(short term after cardioversion)

Reduce recurrences (chronic therapy)

Maximization of Safety

A unique patient-oriented package insert

Cardiology-specific patient newsletter—“Take Heart” by Hope Health

The focus is to maximize patient safety and therapeutic efficacy during ongoing usage

Use of other sotalol formulations will deprive patients of this enhanced safety program

BETAPACE AF™ Provides a Patient Safety Program, Not Just Medication. Every BETAPACE AF Patient Will Receive:

FDA-Mandated Patient Information Includes:

Who should take BETAPACE AF™

How to take BETAPACE AF

Information about possible side effects

Facts about drug interactions

Advice on compliance

d,I-Sotalol vs Placebo for AFib/AFL1,2

27% outpatient initiation.

*In the presence of renal insufficiency (creatinine clearance 40-60 mL/min), patients received the dose QD.†Open-label treatment optional for remainder of 12 months after recurrence.

NDA #19-865.1. Data presented at NASPE Annual Scientific Sessions 5/98. d,l-Sotalol AFib/AFL Multicenter Study Group. Pacing Clin Electrophysiol. 1998;21(Part II):812. Abstract 91.2. Benditt DG et al. Am J Cardiol. 1999;84:270-277.

Outpatient optional for non-SHD

Inpatient mandatory

for SHD

Double-blind treatment for 12 monthsor until recurrence†

Placebo BID*n=69

Sotalol80 mg BID*n=59



RPatients with documented AFib/AFL in past 3 months, now in NSR 57% w/SHD

d,l-Sotalol* vs Placebo for AFib/AFL1

Inclusion Criteria

Adults male or female >18 years with documented symptomatic AFib/AFL within past 3 months currently in NSR

Symptoms defined as 1 or more of the following: palpitations, dizziness, dyspnea, increased sweating, weakness, and chest pain

NDA #19-865.1. Benditt DG et al. Am J Cardiol. 1999;84:270-277.

*BETAPACE AF™: The only sotalol formulation FDA-approved for the treatment of AFib/AFL.

d,I-Sotalol* vs Placebo for AFib/AFL1

Exclusion Criteria Previous use of d,I-sotalol

Asymptomatic AFib/AFL

Contraindications to beta-blocker therapy

CHF

Renal failure (creatinine clearance <40 mL/min)

NDA #19-865.1. Benditt DG et al. Am J Cardiol. 1999;84:270-277.

Oral amiodarone therapy for1 month, within past 12 weeks, or IV amiodarone within previous month

Use of class I AADs or drugs that prolong QT interval

QT >450 msec

History of TdP

Awake sinus heart rate <50 bpm


d,l-Sotalol vs Placebo for AFib/AFL1

Category of Cardiovascular Concomitant MedicationReceived by Subjects During the Initiation Period

Diuretics 14 (20) 13 (22) 9 (14) 7 (11)ACE inhibitors 13 (19) 14 (24) 10 (16) 10 (16)Digitalis 29 (42) 23 (39) 23 (36) 20 (32)Calcium channel-blockers 19 (28) 16 (27) 24 (38) 18 (29)Beta-blockers 17 (25) 14 (24) 10 (16) 10 (16)Oral anticoagulation 34 (49) 28 (48) 27 (43) 31 (50)Antiarrhythmics 0 0 1 (12) 0Any concomitant 59 (86) 51 (86) 52 (82) 46 (74)medicationNDA #19-865.1. Data on file. Berlex Laboratories; 2000.

Placebo 80 mg 120 mg 160 mgCategory (N=69) (N=59) (N=63) (N=62)

d,l-SotalolNumber (%) of Subjects by Treatment Group

d,l-Sotalol vs Placebo for AFib/AFL1

Time to Recurrence of Symptomatic AFib/AFLSince Randomization

Data presented at NASPE Annual Scientific Sessions 5/98.1. Reprinted with permission from Benditt DG et al. Am J Cardiol. 1999;84:270-277.

Log-Rank

0.325

0.018

0.029

Gehan

0.111

0.001

0.012

80 mg:

120 mg:

160 mg:

P Value (d,l-Sotalol vs Placebo)Treatment:Placebo80 mg120 mg160 mg

N at Risk69596362

31354030

29293324

27273121

22232920

21202918

20192717

20152617

19132416

17132215

17132015

16131915

16131914

Placebo80 mg

120 mg160 mg

0 30 60 90 120 150 180 210 240 270 300 330 360 390Time (Days)

Re

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rre

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ree

Su

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al

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

BETAPACE AF™: Efficacy Profile1

*Statistically significant longer time to recurrence compared with placebo (P=0.018 (120 mg), P=0.029 (160 mg).1. Benditt DG et al. Am J Cardiol. 1999;84:270-277.

AFib Freeat 12 months

0

10

20

30

40

50

Placebo

Rel

apse

-Fre

e S

urv

ival

Pro

bab

ilit

y (%

)

n=21

n=69

80

n=22

120

n=31

63

160

n=36

62

Sotalol (mg dose)

59

0

30

60

90

120

150

180

210

240

Placebo 80 120* 160*D

ays

Sotalol (mg dose)

Median Time to Recurrenceat 12 months

d,l-Sotalol* vs Placebo for AFib/AFLTrial1 Summary

Results 120-mg and 160-mg groups significantly more

effective than placebo 120-mg group best benefit:risk ratio No deaths, TdP, sustained VT, VF

Data presented at NASPE Annual Scientific Sessions 5/98.1. Benditt DG et al. Am J Cardiol. 1999;84:270-277.

Most frequent adverse events: Largely reflected beta-blockade

actions and were higher in 160-mggroup than in 120-mg group


BETAPACE AF™: Incidence of Torsade de Pointes Is Dose Related1

100

5

0

<160 mg BID >160 mg BID

Daily Dose

Inci

den

ce

Td

P (

%)

0.0% 0.3%

3.2%

(n=358) (n=597) (n=62)Placebo

*One incidence of torsade de pointes at 80 mg BID occurring at day 1, one incidence of torsade de pointes at 160 mg BID occurring at day 4.1. BETAPACE AF™ (sotalol HCI) prescribing information.

*

Safety 0.3% TdP at doses 160 mg BID in 8 AFib/AFL controlled

clinical trials Very low (0.3%) risk of proarrhythmic events (320 mg/d) in

properly selected patients No additional risk in patients with SHD (without decompensated

heart failure)Efficacy Enhances maintenance of sinus rhythm Longer mean time between recurrences Mild adverse-event profile is well tolerated by most patients

BETAPACE AF™:Proven to Be Safe and Efficacious

BETAPACE AF™ (sotalol HCl) prescribing information.

d,l-Sotalol* Key Points1

Differential class II/III dose-response curves

Renal excretion dose adjustment

Lowers DFTs

Predictable proarrhythmia

*BETAPACE AF™: The only sotalol formulation FDA-approved for the treatment of AFib/AFL.1. Reiffel JA. Am J Cardiol. 2000;85(10A):12D-19D.2. Drug Facts and Comparisons® 2002. St. Louis, Mo:Facts and Comparisons®;2002.

d,l-Sotalol* Key Points (cont)

No noncardiac organ toxicity

Arrhythmia suppression > termination

No increased post-MI mortality, decreased recurrence of MI, post-MI

No pharmacokinetic drug interactions

*BETAPACE AF™ : The only sotalol formulation FDA-approved for the treatment of AFib/AFL.Julian DG et al. Lancet. 1982;1:1142-1147.Physicians’ Desk Reference 2001. Montvale, NJ: Medical Economics Company, Inc.;2001.Reiffel JA. Am J Cardiol. 2000;85(10A):12D-19D.Drug Facts and Comparisons® 2002. St. Louis, Mo:Facts and Comparisons®;2002.

Low Rate of Proarrhythmia With Sotalol in AFib

Dose No. of Author of Study Arrhythmia (mg BID) Patients TdP

Benditt et al. PAF, CAF 80, 120, 160 184 0%

Antman et al. PAF, CAF 80-160 48 0%

Juul-Möller et al. CAF 80 97 1%

Crijns et al. CAF 269±49 39 0%(total daily dose)

Hohnloser et al. CAF 80 on day 1; 160 on 25 0%days 2-7

Singh et al. CAF 40-160 24 0%

Reimold et al. PAF, CAF 80-160 50 0%

Lee et al. PAF 80 38 0%

Wanless et al. AF,SVT 80 or 160 81 0%

Total 586 0.11%

CAF=chronic AF; PAF=paroxysmal AF.Modified from Marcus FI. J Am Coll Cardiol. 1998;32(1):177-180. (Includes all studies other than Benditt.)

Follow-Up Laboratory Tests

Drug Periodic Follow-Up1

Amiodarone TFT, LFT, eyes, PFT, CXR*

Dofetilide Chem 7, ECG (QT)

Sotalol Chem 7, ECG (QT)

Flecainide ECG, r/o CHF, CAD (ETT, Echo)

Propafenone ECG, r/o CHF, CAD (ETT, Echo)

* TFT = Thyroid function tests. LFT = Liver function tests. PFT = Pulmonary function tests.

1. Fuster V et al. J Am Coll Cardiol. 2001;38:1231-1265.2. Drug Facts and Comparisons® 2002. St. Louis, Mo:Facts and Comparisons®;2002.

Follow-Up Laboratory Tests (cont)

Drug Periodic Follow-Up1

Procainamide Chem 7, ECG (QRS, QT), ANA, LE prep, CBC

Quinidine Chem 7, ECG (QRS, QT),LFT, ANA, LE prep, CBC

Disopyramide Chem 7, ECG (QRS, QT)

1. Drug Facts and Comparisons® 2002. St. Louis, Mo:Facts and Comparisons®;2002.

BETAPACE AF™: Dosing Algorithmfor In-Hospital Initiation

• Creatinine clearance (male)=(140-age) x body weight in kg

72 x serum creatinine (mg/dL)

• Creatinine clearance (female)(140-age) x body weight in kg x 0.85

72 x serum creatinine (mg/dL)

When serum concentration is given in µmol/L, divide the value by 88.4 (1mg/dL=88.4 µmol/L)

*Calculation of Creatinine Clearance

Patient on telemetry

BETAPACE AF Contraindicated

QT >450 msec QT 450 msec

Clcr <40 mL/min*

BETAPACE AF Contraindicated 80 mg QD

Clcr 40-60 mL/min* Clcr >60 mL/min*

80 mg BID

• Increase dose as required

• @ maintenance dose, QT must be <500 msec

• observe for 3 days

• Increase dose as required

• @ maintenance dose, QT must be <500 msec

• observe for 5-6 doses

BETAPACE AF™ (sotalol HCl) prescribing information.

BETAPACE AF is indicated for the maintenance of

normal sinus rhythm in patients with symptomatic

AFIB/AFL who are currently in sinus rhythm. Because

BETAPACE AF can cause life-threatening ventricular

arrhythmias, it should be reserved for patients in

whom AFIB/AFL is highly symptomatic.

To minimize the risk of induced arrhythmia, patients initiated or re-initiated on BETAPACE AF should be placed for a minimum of three days (on their maintenance dose) in a facility that can provide cardiac resuscitation, continuous electrocardiographic monitoring and calculations of creatinine clearance. For detailed instructions regarding dose selection and special cautions for people with renal impairment, see DOSAGE AND ADMINISTRATION. Sotalol is also indicated for the treatment of documented, life-threatening ventricular arrhythmias and is marketed under the brand name BETAPACE. BETAPACE, however, should not be substituted for BETAPACE AF because of significant differences in labeling (i.e. patient package insert, dosing administration and safety information).

Pharmacologic_Treatment_of_AFib

Health & Medicine

Transcript of Pharmacologic_Treatment_of_AFib