1. ATRIAL FIBRILLATION IN THE ER MAGDI SAMI, MD,FRCP(C), FACC

2. OBJECTIVES DIAGNOSIS OF DIFFERENT TYPES OF AF AND DIFFERENTIATE FROM OTHER ARRHYTHMIAS DIAGNOSIS OF DIFFERENT TYPES OF AF AND DIFFERENTIATE FROM OTHER ARRHYTHMIAS ACUTE AND LONG-TERM MANAGEMENT OF AF: ACUTE AND LONG-TERM MANAGEMENT OF AF: WHEN TO CARDIOVERT? WHEN TO CARDIOVERT? ELECTRIC VS CHEMICAL ELECTRIC VS CHEMICAL WHEN TO GO FOR RATE-CONTROL? WHEN TO GO FOR RATE-CONTROL? ACUTE & LONG-TERM ACUTE & LONG-TERM

3. CASE 1 Mr. J.V. 60 y old. -Nov.98: first presentation with PAF at age 56. no previous cardiac history except rec. palpitation, no known CRF. -Nov.98: first presentation with PAF at age 56. no previous cardiac history except rec. palpitation, no known CRF. -Physical exam: normal -ECG (show) - Echocardiogram: normal - Lab: SMA normal, high cholesterol

5. What next?

6. Methods to Restore Sinus Rhythm A.Spontaneous cardioversion B.Electrical cardioversion 1. Transthoracic 2. Internal a. intracardiac b. transesophageal c. epicardial C.Pharmacological cardioversion 1. Class 1 A or 1 C 2. Class III

7. Pharmacological Conversion Pharmacological Conversion Class 1 A (quinidine, procainamide, disopyramide) Class 1 A (quinidine, procainamide, disopyramide) Class 1 C (propafenone, flecainide) Class 1 C (propafenone, flecainide) Class III (amiodarone, sotalol, ibutilide, dofetilide) Class III (amiodarone, sotalol, ibutilide, dofetilide) Others Digoxin, beta-blockers, calcium blockers not effective (verapamil may prevent AF recurrences after cardioversion) Others Digoxin, beta-blockers, calcium blockers not effective (verapamil may prevent AF recurrences after cardioversion)

8. Ibutlide Unique iv antiarrhythmic drug Unique iv antiarrhythmic drug Classified as Class III according to Vaughan Williams Classification Classified as Class III according to Vaughan Williams Classification Little effect on conduction in normal cardiac tissue Little effect on conduction in normal cardiac tissue

9. Ibutilide Electrophysiologic Effects No clinically significant effect on QRS No clinically significant effect on QRS Produces a dose related prolongation of the QT interval Produces a dose related prolongation of the QT interval Prolongation of QT interval is similar in men and women Prolongation of QT interval is similar in men and women Prolongs action potential duration and effective refractory periods in both atria and ventricles Prolongs action potential duration and effective refractory periods in both atria and ventricles

10. Ibutilide Electrophysiologic Effects Lengthens effective refractory period in both atrium and ventricle Lengthens effective refractory period in both atrium and ventricle Enhances slow Na + inward plateau current and blocks delayed-rectifier outward K + current Enhances slow Na + inward plateau current and blocks delayed-rectifier outward K + current Maintains Class III effects even at rapid heart rates Maintains Class III effects even at rapid heart rates

11. Ibutilide Mechanism of Action Na V Max +-+- APD Action Potential Duration QRS T QT N Repolarization Slow Na  (Ibutilide) K+K+ Ca plateau (other Class III)

12. Ibutilide Hemodynamic Effects No clinically significant effects on cardiac output, mean pulmonary arterial pressure or capillary wedge pressure in patients with ejection fractions > 35 or 35 or < 35%

13. Ibutilide Pharmacokinetics Similar in all patients regardless of AF or AFL, age, sex, ejection fraction, occurrence of polymorphic ventricular tachycardia or the concomitant use of digoxin, calcium blockers or beta blockers. Similar in all patients regardless of AF or AFL, age, sex, ejection fraction, occurrence of polymorphic ventricular tachycardia or the concomitant use of digoxin, calcium blockers or beta blockers.

14. Ibutilide Pharmacokinetics Pharmacokinetics is highly variable among subjects but linear to dose of 0.01 mg/kg – 0.1 mg/kg (0.6 – 6 mg) Pharmacokinetics is highly variable among subjects but linear to dose of 0.01 mg/kg – 0.1 mg/kg (0.6 – 6 mg) Initial distribution half-life is 1.5 min. and elimination half-life averages 6 h Initial distribution half-life is 1.5 min. and elimination half-life averages 6 h Clearance is primarily hepatic metabolism Clearance is primarily hepatic metabolism

15. Ibutilide Pharmacokinetics Moderate protein binding (40%) Moderate protein binding (40%) 8 metabolites – none of which contribute to its pharmacological effects 8 metabolites – none of which contribute to its pharmacological effects 82% of dose excreted in urine 82% of dose excreted in urine 19 % in faeces 19 % in faeces

16. Ibutilide Indications and Clinical Use Ibutilide (CORVERT ® ) is indicated for the rapid conversion of atrial fibrillation or atrial flutter to sinus rhythm. CORVERT ™ should be considered an alternative to electric cardioversion. Ibutilide (CORVERT ® ) is indicated for the rapid conversion of atrial fibrillation or atrial flutter to sinus rhythm. CORVERT ™ should be considered an alternative to electric cardioversion. CORVERT product monograph

17. Ibutilide Arrhythmia Conversion: Repeat Dose Study Stambler B.S. et al. Circulation 1996; 94:1613

18. Arrhythmia Conversion: Ibutilide vs. Procainamide Arrhythmia Conversion: Ibutilide vs. Procainamide Volgman A.S. et al. J. Am..Coll. Card 1998: 31: 1414

19. Ibutilide Predictors of Arrhthmia Termination * P< 0.05 * Stambler BS. et al. Circulation 1996; 94:1613

20. Ibutilide Proarrythmia Patients with AFIB N/N (%) Patients with AFL N/N (%) All Proarrhythmias 14/340 (4.1%) 35/218 (16%) Non Sustained PVT 9/340 (2.7%) 24/218 (11%) Sustained PVT 4/340 (1.2%) 7/218 (3.2%) % and number of patients with proarrhythmias possibly causally related to ibutlide in three placebo controlled trials CORVERT product monograph

21. Ibutilide Proarrythmia in Cardiac Surgery Patients Patients with AFIB N/N (%) Patients with AFL N/N (%) All Proarrhythmias 8/141 (5.7) 0/77 Non Sustained PVT 3/141 (2.1) 0/77 Sustained PVT 2/141 (1.4) 0/77 % and number of patients with proarrhythmias possibly causally related to ibutlide in placebo controlled trials of AF or AFL in coronary bypass graft or valvular surgery CORVERT product monograph

22. Polymorphic VT Risk Assessment: Independent Predictors of Risk Female gender - 13.2% vs. 3.8% (P = 0.0046) History of heart failure - 11.4% vs. 3.6% (P = 0.0305) Slower heart rate - 78 ± 18 vs. 95 ± 26 bpm (P = 0.0348) Nonwhite race - 15.9% vs. 3.6% (P = 0.0383) Stambler BS. et al. Circulation 1996; 94:1613

23. Ibutilide Dosing Patient Weight Dose Second iv Infusion  60 kg iv infusion over 10 min. 1.0 mg (one 10 ml. Vial) If arrhythmia does not terminate within 10 min. after the end of the initial infusion, a second 10 min. infusion of equal strength maybe given. If arrhythmia does not terminate within 10 min. after the end of the initial infusion, a second 10 min. infusion of equal strength maybe given. < 60 kg iv infusion over 10 min. 0.01 mg/kg ( 0.1 ml/kg) CORVERT product monograph

24. Ibutilide Dosing Post Cardiac Surgery Patient Weight Dose Second iv Infusion  60 kg iv infusion over 10 min. 0.5 mg (5 ml) If arrhythmia does not terminate within 10 min. after the end of the initial infusion, a second 10 min. infusion of equal strength maybe given. < 60 kg iv infusion over 10 min. 0.005 mg/kg ( 0.05 ml/kg) CORVERT product monogram

25. Ibutilide Summary Conversion efficacy Conversion efficacy - AFL 60 – 80%, AF 30 – 50% - AF  arrhythmia duration (46% AF < 7 days vs. 18% AF  7 days) Superior to iv procainamide Superior to iv procainamide Mean time to termination < 30 min. Mean time to termination < 30 min. Lowers atrial DFT, prolongs ARP Lowers atrial DFT, prolongs ARP Enhances efficacy of rapid pacing termination of AFL Enhances efficacy of rapid pacing termination of AFL Proarrhythmia risk (torsade de pointes) Proarrhythmia risk (torsade de pointes) ˜ 2% sustained, 3% non-sustained

26. Ibutilide Electrical vs. Pharmacological Conversion Cardioversion Candidate Atrial Flutter Atrial Fibrillation Duration < 7d Contraindication * to Ibutilide? DC Cardioversion iv Ibutilide YES NO  K + < 4.0mEq/L  HR < 60 bpm  QTc > 440ms  Receiving Class I or III AAD  Hx torsade de pointes or polymorphic VT  Acute MI, unstable angina  Renal failure  Hepatic failure  Pregnancy or breast feeding  SHP < 90 mmHg  Age < 18 years  ECG monitoring  4h post infusion unavailable *

27. CASE 1 (CONT) Pt was started on sotalol 80 mg bid and aspirin. Pt was started on sotalol 80 mg bid and aspirin. Nov. 99 referred because of persistent attacks of irreg. palpitations lasting 3-4 hours, sometimes causing chest and neck pain. Attacks occur once a month. Nov. 99 referred because of persistent attacks of irreg. palpitations lasting 3-4 hours, sometimes causing chest and neck pain. Attacks occur once a month. Pulse 68/min-BP 120/80. exam normal. ECG (n). Pulse 68/min-BP 120/80. exam normal. ECG (n). Sotalol increased to 120 mg bid. Sotalol increased to 120 mg bid.

28. What would you do now?

29. Case 1 (cont) Pt. had a negative Bruce stress test to 10 min(11-12 METS) and 85% MPHR. Pt. had a negative Bruce stress test to 10 min(11-12 METS) and 85% MPHR. Nov 2000, started on flecainide 50 mg. BID in addition to sotalol 120 mg bid. Nov 2000, started on flecainide 50 mg. BID in addition to sotalol 120 mg bid. Pt did not come back until April 2002, complaining of persistent PAF lasting hours at a time and very symptomatic. His meds now include sotalol 80 mg and flecainide 50 mg bid. No coumadin. Pt did not come back until April 2002, complaining of persistent PAF lasting hours at a time and very symptomatic. His meds now include sotalol 80 mg and flecainide 50 mg bid. No coumadin.

30. Case 1 (cont) Pt. refused to take amiodarone opted for rate-control treatment. Started on Tiazac 240 mg/day + coumadin. Pt. refused to take amiodarone opted for rate-control treatment. Started on Tiazac 240 mg/day + coumadin. Sept. 02 still in SR, still complaining about recurrent PAF. Sept. 02 still in SR, still complaining about recurrent PAF.

31. CASE 2 DF 66 Y OLD M HYPERTENSIVE DIABETIC DF 66 Y OLD M HYPERTENSIVE DIABETIC 3 DAYS HISTORY OF FEELING SHORT OF BREATH AND PALPITATIONS 3 DAYS HISTORY OF FEELING SHORT OF BREATH AND PALPITATIONS WAS RELUCTANT TO COME TO ER, WAITED TO SEE HIS GP WHO IMMETIATELY REFERRED HIM TO ER WAS RELUCTANT TO COME TO ER, WAITED TO SEE HIS GP WHO IMMETIATELY REFERRED HIM TO ER INITIAL EXAM SHOWS FAST IRREG. HR, BP 188/90, JVD 10 cm, BILAT. BASAL CREPS. INITIAL EXAM SHOWS FAST IRREG. HR, BP 188/90, JVD 10 cm, BILAT. BASAL CREPS.

33. MANAGEMENT QUESTIONS CV OR RATE CONTROL? CV OR RATE CONTROL? IF CV WHAT TEST TO YOU NEED FIRST? IF CV WHAT TEST TO YOU NEED FIRST? IS CHEMICAL CARDIOVERSION SAFER THAN ELECTRIC? IS CHEMICAL CARDIOVERSION SAFER THAN ELECTRIC? IF RATE CONTROL IS CHOSEN HOW TO PROCEED? IF RATE CONTROL IS CHOSEN HOW TO PROCEED? AFTER THE ACUTE TREATMENT WHAT NEXT? AFTER THE ACUTE TREATMENT WHAT NEXT?

34. WHAT IF THE PATIENT HAD PRESENTED WITH A REGULAR TACHYCARDIA? SEE NEXT SLIDE

36. HOW WOULD YOU TREAT THE PATIENT NOW?

37. CASE 3 24 Y OLD PREGNANT F 33 WKS 24 Y OLD PREGNANT F 33 WKS PRESENTING WITH SEVERE PALPITATIONS AND CHEST PAIN PRESENTING WITH SEVERE PALPITATIONS AND CHEST PAIN HER ARRHYTHMIA STARTED FOR THE FIRST TIME SHORTLY AFTER HER SECOND CUP OF COFFEE AND HAS BEEN GOING ON FOR ONE HOUR. HER ARRHYTHMIA STARTED FOR THE FIRST TIME SHORTLY AFTER HER SECOND CUP OF COFFEE AND HAS BEEN GOING ON FOR ONE HOUR.

39. HOW WOULD YOU TREAT THIS PATIENT?

40. CASE 4 64 Y OLD HYPERTENSIVE F WHO WAS TAKING SOTALOL 80 mg BID FOR PAF 64 Y OLD HYPERTENSIVE F WHO WAS TAKING SOTALOL 80 mg BID FOR PAF SHE RECENTLY VISITED HER GP WHO FOUND HER BP TO BE 160/90 SHE RECENTLY VISITED HER GP WHO FOUND HER BP TO BE 160/90 GP STARTED HER ON 25 MG OF HCTZ QD GP STARTED HER ON 25 MG OF HCTZ QD SINCE THEN PATIENT HAS HAD RECURRENT SYNCOPES AND PRESENTED TO ER SINCE THEN PATIENT HAS HAD RECURRENT SYNCOPES AND PRESENTED TO ER

42. PERSISTANT RECURRENT AF DESPITE MEDICAL Rx R/O PREDISPOSING FACTORS SYMPTOMATIC AV NODE ABLATION/ICD/SURGERY IC: DETERIORATING LVFUNCTION ABLATION NO CHANGE IN LV FUNCTION OBSERVE ASYMPTOMATIC

43. Recommendations for Management of Atrial Fibrillation < 48 Hours Adapted from Golzari H. Ann Intern Med. 1996;125:311-323. Prompt electrical or pharmacologic conversion Control ventricular rate Consider antithrombotic therapy Observe for spontaneous conversion Antiarrhythmic therapy if No antiarrhythmic therapy if Unstable hemodynamics or increased LA size Stable hemodynamics, or first episode, n LA

44. Adapted from Golzari H. Ann Intern Med. 1996;125:311-323. Recommendations for Management of Atrial Fibrillation > 48 Hours Control ventricular rate Start antithrombotic therapy (heparin and/or warfarin or aspirin) Duration < 1 yearDuration > 1 year Warfarin therapy 3-4 weeks Cardioversion or pharmacologic conversion Antiarrhythmic therapy if No antiarrhythmic therapy if Unstable hemodynamics or increased LA size Stable hemodynamics, or first episode, n LA Continue warfarin 1-2 months Monitor for recurrences Chronic antithrombotic therapy Assure control of ventricular rate or