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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
Ap
pro
ved
fo
r A
Fib
Sp
eci f
i c d
osi
ng
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Fi b
Sp
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Fib
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ib
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Pat
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Ph
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/ph
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ity
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ues
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use
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or
AF
ib
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
Sotalol120 mg BID*n=63
Sotalol160 mg BID*n=62
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
*BETAPACE AF™: The only sotalol formulation FDA-approved for the treatment of AFib/AFL.
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
cu
rre
nc
e-F
ree
Su
rviv
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™: The only sotalol formulation FDA-approved for the treatment of AFib/AFL.
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).