Pharmacologic_Treatment_of_AFib

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  • Most patients with symptomatic AFib require therapeutic intervention involving either reduction of symptoms by ventricular rate control (coupled with anticoagulation) or reduction of symptoms by the pursuit of sinus rhythm with the aid of antiarrhythmic agents. Each approach has potential benefits or advantages (pros) and relative disadvantages (cons). These must be considered in making individualized decisions for each patient
  • Pharmacologic_Treatment_of_AFib

    1. 1. Pharmacologic Treatment of AFib <ul><li>Antiarrhythmic Drug </li></ul><ul><li>Pros: </li></ul><ul><ul><li>Maintain normal sinus rhythm/  ectopy </li></ul></ul><ul><ul><li> symptoms </li></ul></ul><ul><ul><li>Improve hemodynamics </li></ul></ul><ul><ul><li> stroke/peripheral embolic risk (??) </li></ul></ul><ul><li>Cons: </li></ul><ul><ul><li>Nuisance side effects </li></ul></ul><ul><ul><li>Organ toxicity </li></ul></ul><ul><ul><li>Proarrhythmia </li></ul></ul><ul><ul><li>Other cardiotoxicity </li></ul></ul><ul><ul><li>Uncertain—persistent need for anticoagulation, rate control </li></ul></ul>?? = still theoretical. <ul><li>Rate Control/Anticoagulate </li></ul><ul><li>Pros: </li></ul><ul><ul><li> symptoms due to increased heart rate </li></ul></ul><ul><ul><li> stroke/peripheral embolic risk </li></ul></ul><ul><ul><li>No serious toxicity/proarrhythmia </li></ul></ul><ul><ul><li>Low cost </li></ul></ul><ul><ul><li>Possible once-a-day dosing </li></ul></ul><ul><li>Cons: </li></ul><ul><ul><li> bleeding risk </li></ul></ul><ul><ul><li>Loss of atrial transport </li></ul></ul>
    2. 2. Antiarrhythmic Agents Approved for the Treatment of AFib <ul><li>IV </li></ul><ul><li>Esmolol (Brevibloc  ): class II </li></ul><ul><li>Diltiazem (Cardizem  ): class IV </li></ul><ul><li>Propranolol (Inderal  ): class II </li></ul><ul><li>Digoxin (Lanoxin  ) </li></ul>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
    3. 3. Drugs Not Approved for Atrial Fibrillation <ul><li>Amiodarone (eg, Cordarone ® ) class III </li></ul><ul><li>Procainamide (eg, Procanbid ® ) class IA </li></ul><ul><li>Disopyramide (eg, Norpace ® ) class IA </li></ul><ul><li>Moricizine (eg, Ethmozine ® ) class I </li></ul><ul><li>Other sotalol formulations class III </li></ul>
    4. 4. 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 CR Dofetilide Amiodarone Quinidine Flecainide Sotalol* Lone AFib Heart Disease Propafenone Disopyramide CR Propafenone Amiodarone Amiodarone Dofetilide CAD Sotalol* HBP Initial Secondary CHF Initial Initial Secondary Initial Secondary
    5. 5. 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 patient safety with BETAPACE AF Approved for AFib Specific dosing for AFib Specific renal function guidelines for AFib Specific QT guidelines for AFib FDA-mandated patient package insert Patient newsletter Formulation substitution inequivalence Physician/pharmacist liability issues if used for AFib Avoidable adverse events due to inappropriate dosing or inadequate patient education and support
    6. 6. Atrial Fibrillation Established Persistent (Requires cardioversion) Permanent (NSR is not/cannot be restored) Paroxysmal-(Self-terminating)
    7. 7. Drug Algorithm for Rate Control in AFib 1 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 CCB BB Digoxin CHF Digoxin  BB CAD BB Digoxin/ CCB* BTS Pindolol Pacer & alternative drug COPD Verapamil Diltiazem Digoxin PVD CCB Digoxin Lone AFib CCB BB Digoxin 1st- Choice Agents: 2nd- Choice Agents: (Based on Efficacy, Tolerance, and Disease Interactions)
    8. 8. AFib: Benefits of Normal Sinus Rhythm Maintenance <ul><li>Relieves symptoms </li></ul><ul><li>Improves ventricular performance/exercise capacity </li></ul><ul><li>Prevents progression or later development of symptoms </li></ul><ul><li>Possibly reduces need for an anticoagulant </li></ul>Fuster V et al. J Am Coll Cardiol. 2001;38:1231-1265.
    9. 9. Goals of Antiarrhythmic Drug Therapy for the Treatment of AFib 1 <ul><li>Accomplish pharmacologic cardioversion </li></ul><ul><li>Facilitate DC cardioversion (class III) </li></ul><ul><li>Maintain NSR to allow reversal of atrial remodeling (short term after cardioversion) </li></ul><ul><li>Reduce recurrences (chronic therapy) </li></ul>1. Reiffel JA. Am J Cardiol . 2000;85(10A):12D-19D.
    10. 10. Maximization of Safety <ul><li>A unique patient-oriented package insert </li></ul><ul><li>Cardiology-specific patient newsletter— “Take Heart” by Hope Health </li></ul><ul><li>The focus is to maximize patient safety and therapeutic efficacy during ongoing usage </li></ul><ul><li>Use of other sotalol formulations will deprive patients of this enhanced safety program </li></ul>BETAPACE AF ™ Provides a Patient Safety Program, Not Just Medication. Every BETAPACE AF Patient Will Receive:
    11. 11. FDA-Mandated Patient Information Includes: <ul><li>Who should take BETAPACE AF ™ </li></ul><ul><li>How to take BETAPACE AF </li></ul><ul><li>Information about possible side effects </li></ul><ul><li>Facts about drug interactions </li></ul><ul><li>Advice on compliance </li></ul>
    12. 12. d,I-Sotalol vs Placebo for AFib/AFL 1,2 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 months or until recurrence † Placebo BID* n=69 Sotalol 80 mg BID* n=59 Sotalol 120 mg BID* n=63 Sotalol 160 mg BID* n=62 R Patients with documented AFib/AFL in past 3 months, now in NSR 57% w/SHD
    13. 13. d,l-Sotalol* vs Placebo for AFib/AFL 1 <ul><li>Inclusion Criteria </li></ul><ul><li>Adults male or female >18 years with documented symptomatic AFib/AFL within past 3 months currently in NSR </li></ul><ul><li>Symptoms defined as 1 or more of the following: palpitations, dizziness, dyspnea, increased sweating, weakness, and chest pain </li></ul>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.
    14. 14. d,I-Sotalol* vs Placebo for AFib/AFL 1 <ul><li>Exclusion Criteria </li></ul><ul><li>Previous use of d,I-sotalol </li></ul><ul><li>Asymptomatic AFib/AFL </li></ul><ul><li>Contraindications to beta-blocker therapy </li></ul><ul><li>CHF </li></ul><ul><li>Renal failure (creatinine clearance <40 mL/min) </li></ul>NDA #19-865. 1. Benditt DG et al. Am J Cardiol. 1999;84:270-277. <ul><li>Oral amiodarone therapy for  1 month, within past 12 weeks, or IV amiodarone within previous month </li></ul><ul><li>Use of class I AADs or drugs that prolong QT interval </li></ul><ul><li>QT >450 msec </li></ul><ul><li>History of TdP </li></ul><ul><li>Awake sinus heart rate <50 bpm </li></ul>*BETAPACE AF ™ : The only sotalol formulation FDA-approved for the treatment of AFib/AFL.
    15. 15. d,l-Sotalol vs Placebo for AFib/AFL 1 Category of Cardiovascular Concomitant Medication Received 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) 0 Any concomitant 59 (86) 51 (86) 52 (82) 46 (74) medication NDA #19-865. 1. Data on file. Berlex Laboratories; 2000. Placebo 80 mg 120 mg 160 mg Category (N=69) (N=59) (N=63) (N=62) d,l-Sotalol Number (%) of Subjects by Treatment Group
    16. 16. d,l-Sotalol vs Placebo for AFib/AFL 1 Time to Recurrence of Symptomatic AFib/AFL Since 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: Placebo 80 mg 120 mg 160 mg N at Risk 69 59 63 62 31 35 40 30 29 29 33 24 27 27 31 21 22 23 29 20 21 20 29 18 20 19 27 17 20 15 26 17 19 13 24 16 17 13 22 15 17 13 20 15 16 13 19 15 16 13 19 14 Placebo 80 mg 120 mg 160 mg 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Time (Days) Recurrence-Free Survival 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
    17. 17. BETAPACE AF ™ : Efficacy Profile 1 *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 Free at 12 months 0 10 20 30 40 50 Placebo Relapse-Free Survival Probability (%) n=21 n=69 Sotalol (mg dose) 59 0 30 60 90 120 150 180 210 240 Placebo 80 120* 160* Days Sotalol (mg dose) Median Time to Recurrence at 12 months 80 n=22 120 n=31 63 160 n=36 62
    18. 18. d,l-Sotalol* vs Placebo for AFib/AFL Trial 1 Summary <ul><li>Results </li></ul><ul><li>120-mg and 160-mg groups significantly more effective than placebo </li></ul><ul><li>120-mg group best benefit:risk ratio </li></ul><ul><li>No deaths, TdP, sustained VT, VF </li></ul>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-mg group than in 120-mg group *BETAPACE AF ™ : The only sotalol formulation FDA-approved for the treatment of AFib/AFL.
    19. 19. BETAPACE AF ™ : Incidence of Torsade de Pointes Is Dose Related 1 < 160 mg BID >160 mg BID Daily Dose Incidence TdP (%) 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. * 100 5 0
    20. 20. BETAPACE AF ™ : Proven to Be Safe and Efficacious <ul><li>Safety </li></ul><ul><li>0.3% TdP at doses  160 mg BID in 8 AFib/AFL controlled clinical trials </li></ul><ul><li>Very low (0.3%) risk of proarrhythmic events (  320 mg/d) in properly selected patients </li></ul><ul><li>No additional risk in patients with SHD (without decompensated heart failure) </li></ul><ul><li>Efficacy </li></ul><ul><li>Enhances maintenance of sinus rhythm </li></ul><ul><li>Longer mean time between recurrences </li></ul><ul><li>Mild adverse-event profile is well tolerated by most patients </li></ul>BETAPACE AF ™ (sotalol HCl) prescribing information.
    21. 21. d,l-Sotalol* Key Points 1 <ul><li>Differential class II/III dose-response curves </li></ul><ul><li>Renal excretion dose adjustment </li></ul><ul><li>Lowers DFTs </li></ul><ul><li>Predictable proarrhythmia </li></ul>*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.
    22. 22. d,l-Sotalol* Key Points (cont) <ul><li>No noncardiac organ toxicity </li></ul><ul><li>Arrhythmia suppression > termination </li></ul><ul><li>No increased post-MI mortality, decreased recurrence of MI, post-MI </li></ul><ul><li>No pharmacokinetic drug interactions </li></ul>*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.
    23. 23. Low Rate of Proarrhythmia With Sotalol in AFib <ul><li>Dose No. of Author of Study Arrhythmia (mg BID) Patients TdP </li></ul><ul><li>Benditt et al. PAF, CAF 80, 120, 160 184 0% </li></ul><ul><li>Antman et al. PAF, CAF 80-160 48 0% </li></ul><ul><li>Juul-Möller et al. CAF 80 97 1% </li></ul><ul><li>Crijns et al. CAF 269±49 39 0% (total daily dose) </li></ul><ul><li>Hohnloser et al. CAF 80 on day 1; 160 on 25 0% days 2-7 </li></ul><ul><li>Singh et al. CAF 40-160 24 0% </li></ul><ul><li>Reimold et al. PAF, CAF 80-160 50 0% </li></ul><ul><li>Lee et al. PAF 80 38 0% </li></ul><ul><li>Wanless et al. AF,SVT 80 or 160 81 0% </li></ul><ul><li>Total 586 0.11% </li></ul>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.)
    24. 24. Follow-Up Laboratory Tests <ul><li>Drug Periodic Follow-Up 1 </li></ul>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.
    25. 25. Follow-Up Laboratory Tests (cont) <ul><li>Drug Periodic Follow-Up 1 </li></ul>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.
    26. 26. BETAPACE AF ™ : Dosing Algorithm for In-Hospital Initiation <ul><li>Creatinine clearance (male)= </li></ul><ul><ul><li>(140-age) x body weight in kg </li></ul></ul><ul><ul><li>72 x serum creatinine (mg/dL) </li></ul></ul><ul><li>Creatinine clearance (female) </li></ul><ul><li>(140-age) x body weight in kg x 0.85 </li></ul><ul><li>72 x serum creatinine (mg/dL) </li></ul><ul><li>When serum concentration is given in µmol/L, divide the value by 88.4 (1mg/dL=88.4 µmol/L) </li></ul>*Calculation of Creatinine Clearance Patient on telemetry BETAPACE AF Contraindicated QT >450 msec QT  450 msec Cl cr <40 mL/min* BETAPACE AF Contraindicated 80 mg QD Cl cr 40-60 mL/min* Cl cr >60 mL/min* 80 mg BID <ul><li>Increase dose as required </li></ul><ul><li>@ maintenance dose, QT must be <500 msec </li></ul><ul><li>observe for 3 days </li></ul><ul><li>Increase dose as required </li></ul><ul><li>@ maintenance dose, QT must be <500 msec </li></ul><ul><li>observe for 5-6 doses </li></ul>BETAPACE AF ™ (sotalol HCl) prescribing information.
    27. 27. <ul><li>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. </li></ul>
    28. 28. <ul><li>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). </li></ul>

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