CCS Atrial Fibrillation Guidelines Management Of AF In

CCS Atrial Fibrillation Guidelines: Management Of AF In 2014: Putting The New Guidelines Into Practice October 2014

About this Slide Set This slide set is a quick-reference tool that features essential diagnostic and treatment recommendations based on the 2010 CCS Atrial Fibrillation Guidelines, the 2012 CCS Atrial Fibrillation Guidelines Update and the 2014 Focused Update of the CCS guidelines for the management of AF. These recommendations are aimed to provide a reasonable and practical approach to care for specialists and allied health professionals obliged with the duty of bestowing optimal care to patients and families, and can be subject to change as scientific knowledge and technology advance and as practice patterns evolve. The guideline is not intended to be a substitute for physicians using their individual judgment in managing clinical care in consultation with the patient, with appropriate regard to all the individual circumstances of the patient, diagnostic and treatment options available and available resources. Adherence to these recommendations will not necessarily produce successful outcomes in every case. For the complete CCS Atrial Fibrillation Guidelines, or for additional resources, please visit our guidelines website at www. ccs. ca Atrial Fibrillation Guidelines

The 2014 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation Co-chairs and Authors Jeff S. Healey and Atul Verma Authors John A. Cairns, Stuart Connolly, Jafna L. Cox, Paul Dorian, David Gladstone, Gordon J. Gubitz, Noah Ivers, Kori Leblanc, Laurent Macle, Michael Sean Mc. Murtry, L. Brent Mitchell, Stanley Nattel, Pierre Pagé, Ratika Parkash, P. Timothy Pollak, Allan C. Skanes, Ian G. Stiell, Mario Talajic, Teresa S. M. Tsang and Carl Van Walraven. Publication date: October www. ccs. ca Atrial Fibrillation Guidelines 2014

Faculty Atul Verma, MD FRCPC FHRS Director of Electrophysiology Research & Labs Southlake Regional Health Centre Assistant Professor, University of Toronto Adjunct Professor, Mc. Gill University John A Cairns, MD, FRCPC, FACC Professor of Medicine Division of Cardiology University of British Columbia Allan C. Skanes, MD FRCPC Associate Professor, Department of Medicine, Division of Cardiology 
Cardiologist, London Health Sciences Centre 
Director, Electrophysiology Lab London Health Sciences Centre www. ccs. ca Atrial Fibrillation Guidelines Jeff Healey, MD, FRCPC Mc. Master University Paul Dorian, MD, FRCPC Department Director, Division of Cardiology University of Toronto Staff Cardiac Electrophysiologist St. Michael's Hospital Professor of Medicine Division of Cardiology and Clinical Pharmacology University of Toronto Staff Scientist at the Li Ka Shing Knowledge Institute. L. Brent Mitchell, MD, FRCPC Professor of Medicine and Cardiac Sciences Libin Cardiovascular Institute of Alberta Health Services and University of Calgary

Overview of the 2014 Update • 2014 publication is meant as an update to prior update in 2012 and original major guideline re-write in 2010 • Includes an executive summary of ALL guidelines from 2010 onwards (updated) which can be downloaded online at the CJC website www. ccs. ca Atrial Fibrillation Guidelines

Overview of the 2014 Update Key new elements of the 2014 Update: • New, simplified stroke risk stratification scheme: “The CCS Algorithm” • Detection of AF in patients with stroke • Investigation and management of subclinical AF • Commentary on left atrial appendage closure • Re-write on cardioversion guidelines in ED • New section on peri-procedural management of oral anticoagulation • New rate/rhythm control algorithm www. ccs. ca Atrial Fibrillation Guidelines

New CCS Algorithm www. ccs. ca Atrial Fibrillation Guidelines

Detection of AF in Stroke Patients www. ccs. ca Atrial Fibrillation Guidelines

Management of SCAF www. ccs. ca Atrial Fibrillation Guidelines

Perioperative Management of OAC • What constitutes low, intermediate and high risk procedures for perioperative bleeding • When interruption of OAC is required and when it is not • How to stop new direct oral anticoagulants around the time of surgery • When and how to bridge for cessation of warfarin therapy • When to restart OAC after surgery www. ccs. ca Atrial Fibrillation Guidelines

New Rate/Rhythm Algorithm www. ccs. ca Atrial Fibrillation Guidelines

Case 1 : Dr. YD AF in Emergency Department by John A. Cairns, MD FRCPC FACC October 2014

Disclosures • DSMBs Chair: AVERROES (apixaban), SHIELD-2 (azimilide), ARTESIA (apixaban) Member: ACTIVE Trials (aspirin, clopidogrel, warfarin), PALLAS (dronedarone), COMPASS (rivaroxaban), • Advisory Boards Boehringer Ingelheim Canada (Since Nov 2010), St Jude Medical (since Jan 2012), Bayer (intermittent), BMS (intermittent) • Research trial funding Medtronic, Sanofi Aventis, Astrazeneca, Bayer, Boston Scientific • Speaker honoraria Boehringer Ingelheim Canada, Lilly, Pfizer/BMS, Bayer www. ccs. ca Atrial Fibrillation Guidelines

Dr. YD, Age 42, Family Practitioner • Last evening he was out celebrating the marriage of his receptionist and consumed about 12 ounces of Johnny Walker Black label. • He went home by taxi, slept poorly and realized this morning about 6: 00 am that his heart rate was rapid and pulse irregular. • He has a mild bitemporal headache and is driven to the ED by his wife. • He has been well, no known hypertension, DM, heart disease, TIA/stroke and no known arrhythmias although he does have mild palpitations from time to time. No COPD or asthma. • In ED: no chest pain, mild SOB, slightly sweaty. HR 140, irregularly irregular, BP 140/90, JVD 4 cm, Chest clear. ECG shows AF, rate 140. www. ccs. ca Atrial Fibrillation Guidelines

Overview of AF Management AF Detected Management of Arrhythmia Assessment of Thromboembolic Risk (CHADS 2) ASA OAC Rate Control No antithrombotic therapy may be appropriate in selected young patients with no stroke risk factors www. ccs. ca Atrial Fibrillation Guidelines Rhythm Control

Dr. YD, Age 42, Family Practitioner How will you manage his rhythm? 1. Electrical cardioversion (150 -200 j) in ED as soon as it can be done. 2. IV metoprolol 5 mg, repeated Q 5 min up to 3 times if rate remains above 110. Home on po metoprolol 50 -100 mg bid if AF persists. 3. IV metoprolol 5 mg, repeated Q 5 min up to 3 times if rate remains above 110. Add propofenone 450 mg po about 10 -15 minutes after first dose of metoprolol if AF persists. 4. IV metoprolol 5 mg, repeated Q 5 min up to 3 times if rate remains above 110. Electrical cardioversion if AF persists. 5. Digoxin 0. 25 mg IV, repeat at 1 hour intervals up to 4 doses if AF persists. www. ccs. ca Atrial Fibrillation Guidelines

Dr. YD, Age 42, Family Practitioner How will you manage his rhythm? 1. Electrical cardioversion (150 -200 j) in ED as soon as it can be done. 2. IV metoprolol 5 mg, repeated Q 5 min up to 3 times if rate remains above 110. Home on po metoprolol 50 -100 mg bid if AF persists. 3. IV metoprolol 5 mg, repeated Q 5 min up to 3 times if rate remains above 110. Add propofenone 450 mg po about 10 -15 minutes after first dose of metoprolol if AF persists. 4. IV metoprolol 5 mg, repeated Q 5 min up to 3 times if rate remains above 110. Electrical cardioversion if AF persists. Best answer! * 5. Digoxin 0. 25 mg IV, repeat at 1 hour intervals up to 4 doses if AF persists. *This is a young man with no stroke risk factors. His AF has been present for only a few hours. It is likely the AF was precipitated by his alcohol indiscretion and he is likely to return to NSR with cardioversion and likely to remain in sinus rhythm. Accordingly, electrical cardioversion is a good option. It makes sense to give IV metoprolol to slow his rate before cardioversion. The cardioversion may be done without prior anticoagulation. He requires no ongoing OAC or ASA. Hence, the best answer is #4. #3 would be acceptable if there is some reason not to do electrical cardioversion, or if there is any expectation that he may have recurrent episodes of AF and might be suitable for a pill in the pocket regimen, but this does not appear indicted in this first presentation of AF. #2 is OK, but in a young person with acute onset, electrical (or pharmacological) cardioversion has a high likelihood of resolving the AF. #1 is not advised since there is no rush to cardiovert him and giving metoprolol will be likely to decrease symptoms prior to cardioversion. #5 would not be a good choice. www. ccs. ca Atrial Fibrillation Guidelines

Dr. YD, Age 42, Family Practitioner How will you reduce his risk of stroke if you decide to cardiovert him? 1. IV LMWH or a NOAC po about 1 hour prior to any cardioversion attempt. 2. IV LMWH or a NOAC po about 1 hour prior to electrical cardioversion, but not required for pharmacologic cardioversion. 3. No anticoagulant required pre cardioversion attempt. 4. Start dabigatran 150 mg bid and have him return for cardioversion after 3 weeks of dabigatran. www. ccs. ca Atrial Fibrillation Guidelines

Dr. YD, Age 42, Family Practitioner How will you reduce his risk of stroke if you decide to cardiovert him? 1. IV LMWH or a NOAC po about 1 hour prior to any cardioversion attempt. 2. IV LMWH or a NOAC po about 1 hour prior to electrical cardioversion, but not required for pharmacologic cardioversion. 3. No anticoagulant required pre cardioversion attempt. Best answer! He is young, has no risk factors for stroke, and the duration of AF has been short. The risk of a stroke with cardioversion and no anticoagulation is very low. He requires no anticoagulation pre cardioversion. 4. Start dabigatran 150 mg bid and have him return for cardioversion after 3 weeks of dabigatran. www. ccs. ca Atrial Fibrillation Guidelines

Management of AF in the ED – Recommendations Is Patient Stable? Immediate Risk for Stroke? Low Risk 1. Clear onset <48 hours, or 2. Therapeutic OAC ≥ 3 wks Pharmacological or electrical CV at 150200 J (Immediate anticoagulation in ED before CV not required) * Antithrombotic therapy YES NO High Risk** No therapeutic OAC ≥ 3 weeks and one of: 1. Onset >48 hours or unknown, or 2. Stroke/TIA <6 months or 3. Mechanical or rheumatic valve disease. Rate-control Therapeutic OAC for 3 weeks before outpatient CV Antithrombotic therapy Unstable – AF causing: 1. Hypotension, or 2. Cardiac ischemia, or 3. Pulmonary edema Trans-esophageal echocardiography (TEE) guided CV Consider urgent electrical CV if rate control not effective Antithrombotic therapy -Initiate OAC upon discharge from - Initiate immediate OAC* in ED (or continue current OAC) if age - Continue OAC for ≥ 4 ED and continue for ≥ 4 ED ≥ 65 or weeks if any ‘high and continue for ≥ 4 weeks after CV CHADS 2 ≥ 1 risk’ ** features present - Early follow-up to review - Early follow-up to -Otherwise, initiate ASA if CAD or Early follow-up to review long-term OAC vascular disease long-term OAC -Early follow-up to review long-term * Immediate OAC = a dose of OAC should be given just prior to cardioversion - either a novel direct oral anticoagulant (NOAC) or a dose of heparin or low molecular OAC with bridging to warfarin if a NOAC is contraindicated. Emergency Management of AF www. ccs. ca Atrial Fibrillation Guidelines

Supporting Data • Post CV TE 0. 8% vs 5. 3% with oral anticoagulation. Prospective cohort study (Bjerkelund et al 1969). • 90% of TE occur within 10 d of CV. Meta-analysis (Berger 1998) • TE < 1% for CV < 48 hrs with no OAC (case series 1997, 2002) • CV > 48 hrs, TE occurs following CV even with OAC (< 1% by 30 days). Rate with NOACs similar to with VKA (NOAC RCTs 2012 -14) www. ccs. ca Atrial Fibrillation Guidelines

Supporting Data • Finnish Study 2014 (Nuotio I et al. JAMA 2014; 312: 647) Rates of TE with duration of AF: <12 hrs: 0. 3%; 12 -24 hrs: 1. 1%; 24 -48 hrs: 1. 1% Multivariable Analysis of Risk Factors for TE (n= 5116) OR(95% CI) P Value Time: 12 -24 vs <12 4. 0 (1. 7 -9. 1) . 001 24 -48 vs <12 3. 3 (1. 3 -8. 9) . 02 Age, y (continuous) 1. 06 (1. 03 -1. 09) <. 001 Female sex 2. 1 (1. 1 -4. 3) . 04 Heart failure 3. 5 (1. 4 -8. 6) <. 001 Diabetes 2. 7 (1. 3 -5. 8) . 01 www. ccs. ca Atrial Fibrillation Guidelines

Dr. YD, Age 42, Family Practitioner How will you reduce his risk of stroke if you decide to cardiovert him? 1. IV LMWH or a NOAC po about 1 hour prior to any cardioversion attempt. 2. IV LMWH or a NOAC po about 1 hour prior to electrical cardioversion, but not required for pharmacologic cardioversion. 3. No anticoagulant required pre cardioversion attempt. 4. Start dabigatran 150 mg bid and have him return for cardioversion after 3 weeks of dabigatran. www. ccs. ca Atrial Fibrillation Guidelines

Dr. YD, Age 42, Family Practitioner How will you reduce his risk of stroke if you decide to cardiovert him? 1. IV LMWH or a NOAC po about 1 hour prior to any cardioversion attempt. 2. IV LMWH or a NOAC po about 1 hour prior to electrical cardioversion, but not required for pharmacologic cardioversion. 3. No anticoagulant required pre cardioversion attempt. Best answer! He is young, has no risk factors for stroke, and the duration of AF has been short. The risk of a stroke with cardioversion and no anticoagulation is very low. He requires no anticoagulation pre cardioversion. 4. Start dabigatran 150 mg bid and have him return for cardioversion after 3 weeks of dabigatran. www. ccs. ca Atrial Fibrillation Guidelines

Dr. YD, Age 42, Family Practitioner How will you reduce his risk of stroke post discharge from Ed? 1. If AF persists, he requires maintenance ASA 81 mg daily at least until follow-up at 1 month. 2. Whether AF persists or resolves, he requires maintenance ASA 81 mg at least until follow-up at 1 month. 3. If AF persists, he requires maintenance OAC at least until follow-up at 1 month. 4. Whether AF persists or resolves, he requires maintenance OAC at least until follow-up at 1 month. 5. Whether AF persists or resolves, he requires no maintenance antithrombotic therapy. www. ccs. ca Atrial Fibrillation Guidelines

Dr. YD, Age 42, Family Practitioner How will you reduce his risk of stroke post discharge from Ed? 1. If AF persists, he requires maintenance ASA 81 mg daily at least until follow-up at 1 month. 2. Whether AF persists or resolves, he requires maintenance ASA 81 mg at least until follow-up at 1 month. 3. If AF persists, he requires maintenance OAC at least until follow-up at 1 month. 4. Whether AF persists or resolves, he requires maintenance OAC at least until follow-up at 1 month. 5. Best Answer! Whether AF persists or resolves, he requires no maintenance antithrombotic therapy. - He is young, has no risk factors for stroke. He fits the CCS algorithm of no antithrombotic therapy for AF. www. ccs. ca Atrial Fibrillation Guidelines

Dr. YD, Age 42, Family Practitioner Within the group of patients with CHADS 2 = 0 (annual stroke risk 1. 9%): • Data from Danish epidemiological studies indicate the following annual risks of stroke: Age 65 -74: 2. 13% Vascular disease: 1. 40% Age < 65, no vascular disease: 0. 7% www. ccs. ca Atrial Fibrillation Guidelines

The “CCS Algorithm” for OAC Therapy in AF Age ³ 65 OAC* YES NO Prior Stroke/SE/TIA or Hypertension or Heart failure or Diabetes Mellitus OAC* YES (CHADS 2 risk factors) **may require lower dosing NO CAD or Arterial vascular disease Consider and modify (if possible) all factors influencing risk of bleeding on OAC (hypertension, antiplatelet drugs, NSAIDs, excessive alcohol, labile INRs) and specifically bleeding risks for NOACs (low e. GFR, age ≥ 75, low body weight)** ASA YES (coronary, aortic, peripheral) NO No Antithrombotic www. ccs. ca * We suggest that a NOAC be used in preference to warfarin for non-valvular AF. Atrial Fibrillation Guidelines

Dr. YD, Age 42, Family Practitioner How will you reduce his risk of stroke post discharge from ED? 1. If AF persists, he requires maintenance ASA 81 mg daily at least until follow-up at 1 month. 2. Whether AF persists or resolves, he requires maintenance ASA 81 mg at least until follow-up at 1 month. 3. If AF persists, he requires maintenance OAC at least until follow-up at 1 month. 4. Whether AF persists or resolves, he requires maintenance OAC at least until follow-up at 1 month. 5. Whether AF persists or resolves, he requires no maintenance antithrombotic therapy. www. ccs. ca Atrial Fibrillation Guidelines

AF Management in the ED Recommendation For patients with no high-risk factors for stroke (recent stroke or TIA within 6 months; rheumatic heart disease; mechanical valve) and clear AF onset within 48 hours or therapeutic OAC therapy for 3 weeks, we recommend that they may undergo cardioversion in the ED without immediate initiation of anticoagulation. After attempted or successful cardioversion, antithrombotic therapy should be initiated as per the CCS algorithm. (Strong Recommendation, Moderate-Quality Evidence) Atrial Fibrillation Guidelines

AF Management in the ED Recommendation For patients at high risk of stroke with cardioversion (not receiving therapeutic OAC therapy for 3 weeks with any of the following: AF episode duration not clearly < 48 hours, stroke or TIA within 6 months, rheumatic heart disease, mechanical valve), we recommend optimized rate control and therapeutic OAC for 3 weeks before and at least 4 weeks after cardioversion. (Strong Recommendation, Moderate-Quality Evidence) Atrial Fibrillation Guidelines

AF Management in the ED Recommendation We suggest that patients at high risk of stroke (not receiving therapeutic OAC therapy for 3 weeks with any of the following: AF episode duration not clearly < 48 hours, stroke or TIA within 6 months, rheumatic heart disease, mechanical valve) may undergo cardioversion guided by transesophageal echocardiography with immediate initiation of intravenous heparin or low molecular weight heparin (LMWH) before cardioversion followed by therapeutic OAC for at least 4 weeks after cardioversion. (Conditional Recommendation, Moderate-Quality Evidence) Atrial Fibrillation Guidelines

AF Management in the ED Recommendation For patients whose recent-onset AF/AFL is the direct cause of instability with hypotension, acute coronary syndrome, or florid pulmonary edema, we recommend that immediate electrical cardioversion be considered with immediate initiation of intravenous or LMWH before cardioversion followed by therapeutic OAC for 4 weeks afterward (unless AF onset was clearly within 48 hours or the patient has received therapeutic OAC for 3 weeks) followed by therapeutic OAC for at least 4 weeks after cardioversion (Strong Recommendation, Low-Quality Evidence) Atrial Fibrillation Guidelines

www. ccs. ca Atrial Fibrillation Guidelines

Case 2 : Mrs. BB Rate and Rhythm Control by Paul Dorian, MD FRCPC October 2014

Disclosures • Paul Dorian has received grant support and honoraria from Bayer, Boehringer-Ingleheim, BMS, Pfizer, Sanofi www. ccs. ca Atrial Fibrillation Guidelines

A guidelines based approach to AF management • Mrs. BB, a 77 year old lady has hypertension, otherwise well • Lives alone, has a dog • On Ramipril 10 mg and bisoprolol 5 mg a day for hypertension • 5 ft 5 in, 190 lbs. • Comes to the office for routine BP follow-up www. ccs. ca Atrial Fibrillation Guidelines

• Pulse rate 85/min, irregular • BP 145/95 , repeated X 3 • No murmurs , no signs CHF • Says she feels well • On closer questioning, she walks the dog around the block; she used to walk to the park, 2 -3 kms away, but “no longer feels like it” • EKG shows AF, otherwise normal, rate 88/min www. ccs. ca Atrial Fibrillation Guidelines

What next? Why does she have AF? 1. Thyroid 2. Hypertension 3. Sleep apnea 4. Ethanol www. ccs. ca Atrial Fibrillation Guidelines

What next? What are the risks and benefits of rhythm control? www. ccs. ca Atrial Fibrillation Guidelines

History Establish Severity (including impact on QOL) Identify Etiology Identify reversible causes (hyperthyroidism, ventricular pacing, SVT, exercise) Identify factors whose treatment could reduce recurrent AF or improve overall prognosis (i. e. hypertension, sleep apnea, left ventricular dysfunction) Identify potential triggers (i. e. alcohol, intensive aerobic training) Identify potentially heritable causes of AF (particularly in lone AF) Determine thromboembolic risk (e. g. CHADS 2 Score) Determine bleeding risk to guide appropriate antithrombotic therapy Review prior pharmacologic therapy for AF, for efficacy and adverse effects www. ccs. ca Atrial Fibrillation Guidelines

Establish AF Severity Use to Guide Therapeutic Approach CCS SAF Score Impact on QOL 0 Asymptomatic 1 Minimal effect on QOL 2 Minor effect of QOL 3 Moderate effect on QOL 4 Severe effect on QOL Dorian et al Can J Cardiol 2006; 22: 383 -386 www. ccs. ca Atrial Fibrillation Guidelines

• SAF class 2 -3 on detailed discussion • Choices: – increase beta blocker – attempt to restore sinus rhythm • CHADS = 2 (CHADSVa. SC 4) • OAC for 3 -4 weeks • Electrical Cardioversion www. ccs. ca Atrial Fibrillation Guidelines

Rhythm Management Recommendations • We recommend that an AV blocking agent should be used in patients with AF or AFL being treated with a class I antiarrhythmic drug (eg, propafenone or flecainide) in the absence of advanced AV node disease (Strong Recommendation, Low Quality Evidence). • We recommend electrical or pharmacologic cardioversion for restoration of sinus rhythm in patients with AF or AFL who are selected for rhythm-control therapy and are unlikely to convert spontaneously (Strong Recommendation, Low Quality Evidence). • We recommend pre-treatment with antiarrhythmic drugs prior to electrical cardioversion in patients who have had AF recurrence post cardioversion without antiarrhythmic drug pre-treatment (Strong Recommendation, Moderate Quality Evidence). www. ccs. ca Atrial Fibrillation Guidelines

Rhythm Management Recommendations • We suggest that patients requiring pacing for the treatment of symptomatic bradycardia secondary to sinus node dysfunction, atrial or dual-chamber pacing be generally used for the prevention of AF (Conditional Recommendation, High Quality Evidence). • We suggest that, in patients with intact AV conduction, pacemakers be programmed to minimize ventricular pacing for prevention of AF (Conditional Recommendation, Moderate Quality Evidence). www. ccs. ca Atrial Fibrillation Guidelines

• How likely is cardioversion to be successful? ( distinguish “success” with IRAF from “failure”) • If sinus rhythm restored , how likely is AF to recur? • What can be done to prevent recurrence? • HT control, ETOH reduction if excessive, sleep apnea treatment if appropriate www. ccs. ca Atrial Fibrillation Guidelines

How do we tell if rhythm control is justified? • Assess QOL without knowing the rhythm or doing an EKG • eg QOL improves post CV, and worsens again with recurrence, vs • No better, or better, but AF recurs without symptoms www. ccs. ca Atrial Fibrillation Guidelines

Major Goals of AF/AFL Arrhythmia Management • Identify and treat underlying structural heart disease and other predisposing conditions • Relieve symptoms • Improve functional capacity/quality of life • Reduce morbidity/mortality associated with AF/AFL ✔ Prevent tachycardia-induced cardiomyopathy ✔ Reduce/prevent emergency room visits or hospitalizations secondary to AF/AFL • Prevent stroke or systemic thromboembolism Recommendations • We recommend that the goals of ventricular rate control should be to improve symptoms and clinical outcomes which are attributable to excessive ventricular rates. (Strong Recommendation, Low Quality Evidence) • We recommend that the goals of rhythm control therapy should be to improve patient symptoms and clinical outcomes, and that these do not necessarily imply the elimination of all AF. (Strong Recommendation, Moderate Quality Evidence) Atrial Fibrillation Guidelines

Rate vs Rhythm Control for Patients with Symptomatic AF SYMPTOMATIC AF Special circumstances in which to consider early rhythm control: Highly symptomatic Multiple recurrences Extreme impairment in QOL Arrhythmia-induced cardiomyopathy ATTEMPT RATE CONTROL Beta-blocker Calcium channel blocker NO Pill in pocket antiarrhythmic therapy CONTINUE RATE CONTROL MODIFY RATE CONTROL - CONSIDER RHYTHM CONTROL Paroxysmal AF Low burden recurrence YES SYMPTOMS RESOLVE Persistent AF High burden recurrence Consider cardioversion Maintenance antiarrhythmic therapy Symptoms improve, don’t change improve, and patient in sinus but AF recurs maintains rhythm and sinus rhythm AF recurs Catheter ablation Observe. If AF recurs, determine if symptomatic Atrial Fibrillation Guidelines

Overview of Rhythm Management Rhythm Control Choices Normal Systolic Function No Hx of CHF Dronedarone+ Flecainide* Propafenone* Sotalol# Rhythm Control Choices Hx of CHF or Left Ventricular Systolic Dysfunction EF > 35% EF ≤ 35% Amiodarone Sotalol** Amiodarone Catheter Ablation Drugs are listed in alphabetical order + Dronedarone should be used with caution in combination with digoxin • Class I agents should be AVOIDED in CAD and should be COMBINED with AV-nodal blocking agents # Sotalol should be used with caution in those at risk for torsades de pointes VT (e. g. female, age > 65 yr, taking diuretics) ** Sotalol should be used with caution with EF 35 -40% and those at risk for torsades de pointes VT (e. g. female, age > 65 yr, taking diuretics) Atrial Fibrillation Guidelines

When, if at all, should antiarrhythmic drugs be used? 1. “Prophylactically “? 2. If AF recurs? www. ccs. ca Atrial Fibrillation Guidelines

If an antiarrhythmic is required, which one? • If no CAD or LV dysfunction • Consider flecainide, propafenone , dronedarone ( cost), sotalol ( fatigue) • Amiodarone usually second line, but in older patients often effective at low doses note: efficacy assessed as: • Patient feels better and has no adverse effects, NOT “ A fib is completely suppressed” www. ccs. ca Atrial Fibrillation Guidelines

Established Patterns and Severity of Atrial Fibrillation Patterns of Atrial Fibrillation SAF Score Newly Diagnosed AF Paroxysmal: Selfterminating <7 d SAF Score* Class 0 Persistent: Sustained ≥ 7 d Permanent: Decision to continue in AF Impact on QOL** Asymptomatic 1 Minimal effect on QOL 2 Minor effect on QOL 3 Moderate effect on QOL 4 Severe effect on QOL * Dorian P, Cvitkovic SS, Kerr CR; et al. Can J Cardiol. 2006; 22(5): 383 -386 Atrial Fibrillation Guidelines ** QOL = quality of life

Overview of AF Management AF Detected Assessment of Thromboembolic Risk (CHADS 2) Appropriate Antithrombotic Therapy Detection and Treatment of Precipitating Causes Management of Arrhythmia Rate Control Atrial Fibrillation Guidelines Rhythm Control

Overview of Rate Management Rate Control Drug Choices Heart Failure CAD No Heart Failure or CAD β-blocker ± Digoxin β-blocker* Calcium Channel Blocker# Combination Rx β-blocker* Calcium Channel Blocker# Digoxin† Combination Rx Drugs are listed in alphabetical order *β-blockers preferred in CAD # Non-dihydropyridine calcium channel blockers (diltiazem, verapamil) †Digoxin may be considered as monotherapy only in particularly sedentary individuals Atrial Fibrillation Guidelines

Managing Rate Control - Recommended Drugs ß-Blockers Drug Dose Adverse Effects Atenolol 50 - 150 mg p. o. daily bradycardia, hypotension, fatigue, depression Bisoprolol 2. 5 - 10 mg p. o. daily as per atenolol Metoprolol 25 mg - 200 mg p. o. bid as per atenolol 20 - 160 mg p. o daily - bid as per atenolol 80 - 240 mg p. o. tid as per atenolol Nadolol Propranolo l Calcium Channel Blockers and Digoxin Drug Dose Adverse Effects Verapamil 120 - 480 mg p. o. daily 120 - 240 mg p. o. bid bradycardia, hypotension, constipation Diltiazem 120 - 480 mg p. o. daily 120 - 240 mg p. o. bid bradycardia, hypotension, ankle swelling 0. 0625 mg - 0. 25 mg p. o. daily bradycardia, nausea, vomiting, visual disturbance Digoxin Atrial Fibrillation Guidelines

Managing Rhythm Control - Recommended Drugs Drug/Do se Effica cy Flecainide 50 -150 mg BID 30 -50% Propafenon e 150 -300 mg TID 30 -50% Amiodarone 100 -200 mg OD (after 10 g loading) Dronedaron e 400 mg BID 60 -70% 40% Toxicity Ventricular tachycardia Bradycardia Rapid ventricular response to AF or atrial flutter (1: 1 conduction) Abnormal taste Photosensitivity, Bradycardia, GI upset, Thyroid dysfunction, Hepatic toxicity, Neuropathy, Tremor, Pulmonary toxicity, Torsades de pointes (rare) GI upset Bradycardia Hepatic toxicity Comments Contraindicated in patients with CAD or LV dysfunction Should be combined with an AV nodal blocking agent Low risk of proarrhythmia Limited by systemic side effects Most side effects are dose & duration related Should not be used for rate control or for rhythm control in patients with a history of CHF or LV EF < 40%. Should be used with caution when added to digoxin. Liver enzyme monitoring required. New agent – limited experience outside clinical trials. Should be avoided in patients at high risk of torsades Sotalol Atrial Fibrillation Guidelines Torsades de pointes VT – especially women >65 years taking

Rhythm Management Recommendations • We recommend the optimal treatment of precipitating or reversible predisposing conditions of AF prior to attempts to restore or maintain sinus rhythm (Strong Recommendation, Low Quality Evidence). • We recommend a rhythm-control strategy for patients with AF or AFL who remain symptomatic with rate-control therapy or in whom rate-control therapy is unlikely to control symptoms (Strong Recommendation, Moderate Quality Evidence). • We recommend that the goal of rhythm-control therapy should be improvement in patient symptoms and clinical outcomes, and not necessarily the elimination of all AF (Strong Recommendation, Moderate Quality Evidence). • We recommend use of maintenance oral antiarrhythmic therapy as first-line therapy for patients with recurrent AF in whom long-term rhythm control is desired (see Figures) (Strong Recommendation, Moderate Quality Evidence). • We recommend intermittent antiarrhythmic drug therapy (“pill in the pocket”) in symptomatic patients with infrequent, longer-lasting episodes of AF or AFL as an alternative to daily antiarrhythmic therapy (Strong Recommendation, Moderate Quality Evidence). • We recommend that oral antiarrhythmic drug therapy should be avoided in patients with AF or AFL and advanced sinus or AV nodal disease unless the patient has a pacemaker or implantable defibrillator (Strong Recommendation, Low Quality Evidence). Atrial Fibrillation Guidelines

Rhythm Management – Recommendations and Practical Tip Recommendations • We recommend that dronedarone not be used in patients with permanent AF nor for the sole purpose of rate control (Strong Recommendation, High Quality Evidence). • We recommend dronedarone not be used in patients with a history of heart failure or a left ventricular ejection fraction <0. 40 (Strong Recommendation, Moderate Quality Evidence). • We suggest dronedarone be used with caution in patients taking digoxin (Conditional Recommendation, Moderate Quality Evidence). Practical Tip: Dronedarone is a reasonable choice for rhythm control in selected patients with AF. Typically, these would be patients with nonpermanent (predominantly paroxysmal) AF with minimal structural heart disease. Consideration should be given to monitoring for liver enzyme elevations within 6 months of initiating therapy with dronedarone. Atrial Fibrillation Guidelines

Strategy of rhythm-control for recent-onset AF/AFL Clear onset <48 h or Therapeutic OAC 2 x 3 weeks Hemodynamically unstable Urgent electrical CV at 150 -200 J Hemodynamically stable Pharmacological or electrical CV at 150 -200 J Antithrombotic therapy - No prior anticoagulation required - Initiate OAC in ED if CHADS 2 >1 or age >65 - Otherwise, initiate ASA if CAD or vascular d. - Early follow-up to review long-term OAC 1 High-risk patients 1 or Onset >48 h or unknown or Inadequate OAC 2 Rate-control Therapeutic OAC for 3 weeks before CV Trans-esophageal echocardiography (TEE) guided CV 3 Antithrombotic therapy - Initiate or continue OAC for >4 weeks - Early expert follow-up to review long-term OAC risk of stroke (e. g. mechanical valve, rheumatic heart disease, recent stroke/TIA) 2 OAC = oral anticoagulant; N-OAC = Novel OAC (dabigatran, apixaban, rivaroxaban) 3 Immediate N-OAC preferred, but if N-OAC contraindicated use warfarin with heparin bridging

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Case 3 : Mr. MB Stroke Prevention by John A. Cairns, MD FRCPC FACC October 2014

Dr. Fred Brown, a GP colleague, asks for your advice about Mr. MB, Age 67 Heart “skipping beats” and “racing”, especially on exertion – 2 weeks prior to GP visit • • Previously well, active, no significant limitations No hypertension, DM, CHF, no meds HR 100 irreg, BP 135/85 HS normal, no murmurs or gallops, JVP just visible at 45° www. ccs. ca Atrial Fibrillation Guidelines

Dr. Fred Brown, a GP colleague, asks for your advice about Mr. MB, Age 67 (cont’d) • • • Hgb 145, Glucose 5. 4, Cr 1. 0 (e. GFR 110) EKG – AF 95/min Echo – unremarkable (LA 4. 0, LV 5. 0, EF 55%, no LVH) Dr. Brown started him on atenolol 50 mg qam and symptoms are much improved www. ccs. ca Atrial Fibrillation Guidelines

Mr. MB, Age 67 yr, 1 week post atenolol 50 mg qam

How would you treat him to reduce his risk of stroke? 1. No antithrombotic therapy ? 2. ASA 81 mg/day ? 3. OAC ? www. ccs. ca Atrial Fibrillation Guidelines

How would you treat him to reduce his risk of stroke? 1. No antithrombotic therapy ? 2. ASA 81 mg/day ? 3. OAC ? Best answer! This 67 year old man fits the CCS algorithm for use of OAC. The new algorithm looks first at age and if the person is age ≥ 65 years, OAC is indicated, provided the risk of major bleeding is not excessive. www. ccs. ca Atrial Fibrillation Guidelines

What is Mr. MB’s CHADS 2 score? 1. 1 2. 2 3. 0 4. 3 What is his annual risk of stroke? 1. 0. 5% ? 2. 1. 0% ? 3. 2. 0% ? 4. 5. 0% ? www. ccs. ca Atrial Fibrillation Guidelines

What is Mr. MB’s CHADS 2 score? 1. 1 2. 2 3. 0 – Best answer! His CHADS 2 score is 0. Note in CHADS 2 no points are given for age until the patient is ≥ 75 years. 4. 3 What is his annual risk of stroke? 1. 0. 5% ? 2. 1. 0% ? 3. 2. 0% ? Best answer! His annual risk of stroke at age 67 is about 2. 13 % (mean risk for CHADS 2 score of 0 is 1. 9%, but his risk at age 67 is higher than the mean in this category). 4. 5. 0% ? www. ccs. ca Atrial Fibrillation Guidelines

Stroke rate/ 100 patient yr Risk Factor Score Congestive Heart Failure 1 Hypertension 1 Age ≥ 75 1 Diabetes Mellitus 1 Stroke/TIA/ Thromboembolism 2 Maximum Score 6 www. ccs. ca Atrial Fibrillation Guidelines 1. 9% CHADS 2

Mr. MB, Age 67 BUT, within the group of patients with CHADS 2 = 0 (annual stroke risk 1. 9%): • Data from Danish epidemiological studies indicate the following annual risk of stroke: Age 65 -74: 2. 13% Vascular disease: 1. 40% Age < 65, no vascular disease: 0. 7% www. ccs. ca Atrial Fibrillation Guidelines

The “CCS Algorithm” for OAC Therapy in AF Age ³ 65 OAC* YES NO Prior Stroke/SE/TIA or Hypertension or Heart failure or Diabetes Mellitus OAC* YES (CHADS 2 risk factors) **may require lower dosing NO CAD or Arterial vascular disease Consider and modify (if possible) all factors influencing risk of bleeding on OAC (hypertension, antiplatelet drugs, NSAIDs, excessive alcohol, labile INRs) and specifically bleeding risks for NOACs (low e. GFR, age ≥ 75, low body weight)** ASA YES (coronary, aortic, peripheral) NO No Antithrombotic www. ccs. ca * We suggest that a NOAC be used in preference to warfarin for non-valvular AF. Atrial Fibrillation Guidelines

How would you treat him to reduce his risk of stroke? 1. No antithrombotic therapy ? 2. ASA 81 mg/day ? 3. OAC ? www. ccs. ca Atrial Fibrillation Guidelines

How would you treat him to reduce his risk of stroke? 1. No antithrombotic therapy ? Incorrect. Given his 2. 1% annual risk of stroke it would be wise to prescribe antithrombotic therapy. 1. ASA 81 mg/day ? Incorrect. Probably inadequate protection. His stroke risk would be reduced by about 20%, with an annual risk of major bleeding of about 0. 5%. 1. OAC ? Correct! Best choice. OAC recommended by CCS Guidelines. www. ccs. ca Atrial Fibrillation Guidelines

What about bleeding risk? What would be his annual risk of bleeding on OAC? 1. 0. 5%? 2. 1%? 3. 3% 4. 5% www. ccs. ca Atrial Fibrillation Guidelines

What about bleeding risk? What would be his annual risk of bleeding on OAC? 1. 0. 5%? 2. 1%? – Best answer! This comes from the HAS-BLED score, which gives him 1 point for being over age 65. 3. 3% 4. 5% www. ccs. ca Atrial Fibrillation Guidelines

www. ccs. ca Atrial Fibrillation Guidelines

The “CCS Algorithm” for OAC Therapy in AF Age ³ 65 OAC* YES NO Prior Stroke/SE/TIA or Hypertension or Heart failure or Diabetes Mellitus OAC* YES (CHADS 2 risk factors) **may require lower dosing NO CAD or Arterial vascular disease Consider and modify (if possible) all factors influencing risk of bleeding on OAC (hypertension, antiplatelet drugs, NSAIDs, excessive alcohol, labile INRs) and specifically bleeding risks for NOACs (low e. GFR, age ≥ 75, low body weight)** ASA YES (coronary, aortic, peripheral) NO No Antithrombotic www. ccs. ca * We suggest that a NOAC be used in preference to warfarin for non-valvular AF. Atrial Fibrillation Guidelines

Prevention of Stroke in AF/AFL Stratification of patients using a predictive index for stroke risk Recommendation We recommend that all patients with AF or AFL (paroxysmal, persistent or permanent), should be stratified using a predictive index for stroke risk (for example, the “CCS algorithm” based on the CHADS 2 model). (Strong Recommendation, High Quality Evidence) Atrial Fibrillation Guidelines

Prevention of Stroke in AF/AFL OAC therapy for patients ≥ 65 year or CHADS 2 ≥ 1 Recommendation We recommend that OAC therapy be prescribed for most patients with age ≥ 65 years or CHADS 2 ≥ 1 (the “CCS algorithm”) (Strong Recommendation, Moderate Quality Evidence) Atrial Fibrillation Guidelines

For Mr. MB, age 67, the GP is asking: “If I prescribe an OAC, which should I choose? ” 1. Warfarin to achieve INR 2 -3 ? 2. Rivaroxaban 20 mg daily ? 3. Dabigatran 150 mg bid or Dabigatran 110 mg bid? 4. Apixaban 5 mg bid ? 5. Any of 2, 3 or 4, although not all are equivalent? Atrial Fibrillation Guidelines

Stroke or systemic embolic events in large NOAC trials, vs warfarin Dabi 150 mg Rivaroxaban Apixaban Edox 60 mg Ruff et al. , The Lancet, 2013

Major bleeding events in large NOAC trials, vs warfarin RE-LY 150 mg 60 mg Ruff et al. , The Lancet, 2013

Secondary efficacy and safety outcomes in large NOAC trials, vs. warfarin Efficacy Ruff et al. , The Lancet, 2013

Prevention of Stroke in AF/AFL Most patients should receive a NOAC Recommendation We recommend that when OAC-therapy is indicated for patients with nonvalvular AF, most patients should receive dabigatran, rivaroxaban, apixaban or edoxaban (when approved) in preference to warfarin. (Strong Recommendation, High Quality Evidence) Atrial Fibrillation Guidelines

For Mr. MB, age 67, the GP is asking: “If I prescribe an OAC, which should I choose? ” 1. Warfarin to achieve INR 2 -3 ? Correct! An acceptable therapy since OAC is indicated. Warfarin will reduce risk by 2/3, but complex to use. 2. Rivaroxaban 20 mg daily ? Correct! A preferred therapy. Non-inferior to warfarin and easier to use. 3. Dabigatran 150 mg bid or Dabigatran 110 mg bid? Correct! A preferred therapy. Superior to warfarin and easier to use. Dabigatran 110 mg bid Correct! An acceptable therapy. Non-inferior to warfarin. Easier to use. 4. Apixaban 5 mg bid ? Correct! A preferred therapy. Superior to warfarin and easier to use. 5. Any of 2, 3 or 4, Best answer. All are acceptable therapies, but the NOACs are preferred over warfarin, and the features of the individual NOACs vary. Atrial Fibrillation Guidelines

www. ccs. ca Atrial Fibrillation Guidelines

Case 4: the pediatrician and Case 5 : the young patient Catheter Ablation by Allan C. Skanes, MD FRCPC October 2014

Disclosures Knowledge Translation work with: • Boehringer-Ingelheim • Bayer • Pfizer Research Grants with: • Boehringer-Ingelheim • Biosense Webster Atrial Fibrillation Guidelines

Case 4 66 year-old pediatrician with intermittent palpitations for last 6 -8 months • Strong palpitations, SOB, mild CP • Long episodes he finds it hard to finish clinic • To ED once where rapid AF documented • Underwent DC cardioversion • Put on Bisoprolol 2. 5 mg daily and titrated to 5 mg daily Atrial Fibrillation Guidelines

Case 4 Has had high blood pressure readings recorded intermittently but “is not hypertensive” Agitated he had to wait. PMHx: None On ASA and Bisoprolol Avid cyclist Overweight but denies snoring / apneic breathing States “I do not have sleep apnea” HR 80 bpm BP 165/90 Otherwise exam is normal • Echo: essentially normal – LA slightly enlarged 42 mm – LV function normal, EF 60%, no WMA, no LVH Atrial Fibrillation Guidelines

Case 4 Has read about ablation and wants “cryoballoon” ablation – he has read that this is the newest breakthrough Doesn’t want drugs because they will cloud his sensorium and effect his ability to do clinic. Atrial Fibrillation Guidelines

Your advice for Case 4? 1. Discuss PV isolation in detail – refer for PVI 2. Strongly suggest add flecainide to bisoprolol 3. Refer him to EP for further discussion 4. Suggest he take amiodarone and if fails - ablation Atrial Fibrillation Guidelines

Your advice for Case 4? 1. Discuss PV isolation in detail – refer for PVI 2. Strongly suggest add flecainide to bisoprolol – Best answer! The latest CCS AF Guidelines suggest that anti-arrhythmic drugs be given an opportunity for rhythm control prior to AF ablation. Although there is evidence that AF ablation as a first line therapy is effective, the data are mixed and the complication rate is, in most operators opinion too large to do this on a routine basis. There may be rare exceptions where AF ablation is considered prior to trials of anti-arrhythmic drugs, but these should be rare and individualized with full patient informed consent. The choice of anti-arrhythmic drugs as first line could be either flecainide or amiodarone, although amiodarone is not usually first line. Flecainide would probably be my choice over amiodarone, as long as there is no evidence of coronary disease and it would be acceptable to the patient to take it as well as a AV node blocking agent such as a beta blocker or diltiazem. Sotalol and amiodarone are reasonable monotherapies for AF. 3. Refer him to EP for further discussion – Probably, most popular answer! 4. Suggest he take amiodarone and if fails - ablation Atrial Fibrillation Guidelines

AF Ablation as first line therapy MAANTRA PAF Study N Eng J Med 2012; 367: 1587 -95 N=294 Baseline p=0. 007 3 mths 6 mths 12 mths Atrial Fibrillation Guidelines 18 mths 24 mths

RAAFT 2 Study: 1 st line AF Ablation Time to First recurrence of symptomatic/asymptomatic AF/AT/AFl n=127 72. % 55% HR: 0. 56 (0. 35 – 0. 90) p= 0. 02 Morillo C et al. JAMA. 2014 Feb 19; 311(7): 692 -700 Atrial Fibrillation Guidelines

Worldwide AF Ablation (’ 03 -’ 06) Type of Complication (n=14, 218) Femoral pseudoaneurysm AV fistulae Pneumothorax No of Pts 152 88 15 Rate% 0. 93 0. 54 0. 09 Valve damage/requiring surgery 11/7 0. 07 Tamponade Transient ischaemic attack PV stenosis requiring intervention Stroke Permanent diaphragmatic paralysis Death Atrium-esophageal fistulae 213 115 48 37 28 25 3 1. 31 0. 71 0. 29 0. 23 0. 17 0. 15 0. 02 TOTAL 741 4. 54% Cappato R et al. Circ Arrhythm Electrophysiol. 2010; 3: 32 -8 Atrial Fibrillation Guidelines

Ablation Recommendations • We recommend catheter ablation of AF in patients who remain symptomatic following adequate trials of anti-arrhythmic drug therapy and in whom a rhythm control strategy remains desired. (Strong Recommendation, Moderate Quality Evidence) • We suggest catheter ablation to maintain sinus rhythm as first-line therapy for relief of symptoms in highly selected patients with symptomatic, paroxysmal AF. (Conditional Recommendation, Low Quality Evidence) Values and Preferences: These recommendations recognize that the balance of risk with ablation and benefit in symptom relief and improvement in quality of life must be individualized. They also recognize that patients may have relative or absolute cardiac or non-cardiac contra-indications to specific medications. Atrial Fibrillation Guidelines

Comparison of North American and European Guidelines CCS Guidelines ESC Guidelines ACCF/AHA/HRS Strength Level of Evidence Class Level of Evidence Paroxysmal* Conditional Moderate IIa (Conditional) A (High) I (Strong)¶ A (High) Persistent* Conditional Moderate IIa (Conditional) B (Moderate) IIa (Conditional) A (High) Failed 1 drug Conditional Moderate -- -- I (Strong)¶ A (High) Strong Moderate -- -- Conditional Low IIb (Conditional) B (Moderate) -- -- -- IIb (Conditional) A (High) Failed ≥ 2 drugs 1 st Line PAF / sign. structural heart disease * Applies to patients with symptomatic AF and failed at least one anti-arrhythmic drug. ¶ Dictates ablation performed in experienced centre in patient with minimal heart disease -- Not directly addressed. Often this group is incorporated into other recommendations Atrial Fibrillation Guidelines

Case 4 • Agrees to add flecainide 50 mg bid to bisoprolol • Recurrent episodes of AF – but shorter • Flecainide increased to 100 mg bid • Episodes on average 1 / month lasting 45 -90 minutes • “Very bothered by spells” although does not limit work or personal activities Atrial Fibrillation Guidelines

Thermacool study: Freedom from PAF Wilber DJ et al JAMA 2010; 303: 333 Atrial Fibrillation Guidelines

Systematic Review of RCTs of Ablation vs Rx Ablation 28/32 Control 13/35 OR 11. 85 95% CI 3. 4 -41. 4 12/15 6. 0 1. 2 -30. 7 46/53 13/59 23. 3 8. 5 -63. 6 85/99 24/99 19. 0 9. 2 -39. 3 38/68 6/69 13. 3 5. 1 -34. 9 266/344 102/346 15. 8 10. 1 -24. 7 • 9 RCTs / 3 systematic reviews in 1274 patients who have failed ≥ 1 drug • uniformly demonstrate large differences in recurrence of AF • (OR 9. 74 95% CI, 3. 98 to 23. 87) in favour of ablation vs AAD Piccini JP et al. Circ Arrhythm 2009; 2: 626 Atrial Fibrillation Guidelines

Contact Force / Cryoablation Technological Advances Improved outcomes Improved sustainability Improved safety Atrial Fibrillation Guidelines

Contact Force / Cryoablation Technological Advances Improved outcomes Improved sustainability Improved safety Reddy VY et al. Heart Rhythm 2012; 9: 1789 – 1795 Atrial Fibrillation Guidelines

Posterior LA as source of Triggering beats and Circular activity Atrial Fibrillation Guidelines

Tachycardia in Right Veins ECG Lead II Right Veins CS Atrial Fibrillation Guidelines

AF Ablation lesion set Atrial Fibrillation Guidelines

Tachycardia in Right Veins: Behind Fence II R L P V PV Tachycardia CS Atrial Fibrillation Guidelines PV Isolation

Why do patient need a repeat procedure? Atrial Fibrillation Guidelines

Case 4 • Doing well 3 months after ablation – No recurrent symptoms – Loop recorder shows occ. PACs but no AF • 66 year old man with “hypertension” despite his assurances (CHADS 2=1) Atrial Fibrillation Guidelines

What would you recommend for Case 4 at this point? 1. Continue OAC (dabigatran 150 mg bid) 2. Stop dabigatran Atrial Fibrillation Guidelines

What would you recommend for Case 4 at this point? 1. Continue OAC (dabigatran 150 mg bid) Refer to practical tips in next slide. 2. Stop dabigatran This is an area of intense debate and there is no correct answer! Studies of long-term monitoring have consistently shown asymptomatic episodes of AF both prior to and following ablation. Symptoms are therefore not a good guide for the presence or absence of AF. It is the standard of practice in many centers internationally to stop the OAC at this stage. However, the need for OAC after a “successful” ablation has not been rigourously tested in large randomized trials. These trials have been proposed. Obviously, repeat monitoring would be required to document the absence of asymptomatic AF, although documentation of complete elimination of AF may be impossible. At this stage, I would leave this decision to the electrophysiologist involved. He or she may choose to continue the OAC for a period of time in the absence of clear data. Most would agree that if the CHADS-VASc score was 0 (1 in female) OAC should be discontinued. It would not be recommended if AF were present. If the CHADS score was 2 or greater, most would continue the OAC indefinitely. A range of opinions would be expressed for intermediate scores. Atrial Fibrillation Guidelines

Practical Tips • AF ablation should not be considered as an alternative to oral anticoagulation. • If a patient has a high thromboembolic risk profile, then the patient should continue oral anticoagulation even after successful AF ablation. • Studies of long-term monitoring have consistently shown asymptomatic episodes of AF both prior to and following ablation • Initiation of oral anticoagulation should also not be delayed when indicated in patients pending referral for AF ablation. Atrial Fibrillation Guidelines

Case 5 46 year-old referred because pre-op ECG shows AF Having ACL/MCL fixed • Completely unaware of his heart • Good exercise tolerance • PMHx: Hypertension on perindopril and bisoprolol • Obese BMI 36 Atrial Fibrillation Guidelines

Case 5 HR in office is 89, BP 145/85 Exam normal Echo LV normal size function EF 55 -60% LA 45 mm – mild MR Hb. A 1 C 8. 6% Atrial Fibrillation Guidelines

What do you recommend for Case 5? 1. Holter to assess rate control 2. OAC of your choice (__ban / __tran) 3. ASA Atrial Fibrillation Guidelines

What do you recommend for Case 5? 1. Holter to assess rate control 2. OAC of your choice (__ban / __tran) – Best answer! The patient’s heart rate in the office at rest is adequate, ie < 100 bpm, and he is without symptoms. He meets guideline recommendations for rate control. A Holter monitor to assess his rate control is not necessary, but not unreasonable to document adequate rate control throughout his daily activities. It is also reassuring that his LV function is normal or near normal and he has no evidence of tachycardiainduced cardiomyopathy. The patient has hypertension. Despite his young age, he should be on an OAC – either warfarin or one of the new OACs. . ASA is insufficient protection from stroke. 3. ASA Atrial Fibrillation Guidelines

Case 5 Returns to see you in 3 months Holter AF throughout mean rate 89 (48 – 126) 3 runs of NSVT or aberrancy Wants to discuss ablation with you to get: 1. back in shape 2. off OAC Atrial Fibrillation Guidelines

What options do you offer Case 5 at this point? 1. Refer for ablation 2. Counsel about diet and arrange F/U 6 mos 3. Refer for cardioversion and ablation 4. Arrange for sleep study first Atrial Fibrillation Guidelines

What options do you offer Case 5 at this point? 1. Refer for ablation 2. Counsel about diet and arrange F/U 6 mos – Best answer!The patient’s goal to get in shape and off OAC is best met with ongoing lifestyle management. It is important to point out that catheter ablation is not a verified approach to replace OAC in someone who would otherwise need it. Although it makes intuitive sense to patients – that is” fix the fib then I don’t need to take the blood thinner” – this is not evidence based. Catheter ablation is a symptom-driven procedure that has little to offer a truly asymptomatic patient. Consideration of obstructive sleep apnea (OSA) is important. Usually prior to a full sleep study, screening for sleep apnea is worthwhile. There are occasions when patient’s symptoms are hard to attribute to AF. Under these circumstances, we have performed DC cardioversion to determine if patients feel better in sinus rhythm and are aware if they return to AF. If so, there may be some benefit to catheter ablation. In this man’s case, he is completely asymptomatic. As such, catheter ablation is not indicated. 3. Refer for cardioversion and ablation 4. Arrange for sleep study first Atrial Fibrillation Guidelines

Practical Tips • AF ablation should not be considered as an alternative to oral anticoagulation. • If a patient has a high thromboembolic risk profile, then the patient should continue oral anticoagulation even after successful AF ablation. • Studies of long-term monitoring have consistently shown asymptomatic episodes of AF both prior to and following ablation • Initiation of oral anticoagulation should also not be delayed when indicated in patients pending referral for AF ablation. Atrial Fibrillation Guidelines

Documented AF > 30 seconds after one procedure with or without AAD Results – Persistent AF p=0. 15 59% 48% 44% Verma et al presented ESC 2014 Atrial Fibrillation Guidelines

Atrial Fibrillation Guidelines

Case 6 – Mr. OP Peri-Procedure by L. Brent Mitchell, MD FRCPC October 2014

Disclosures Dr. L. Brent Mitchell has received grant support and/ or honoraria from: • • www. ccs. ca Bayer Boehringer-Ingelheim Bristol-Myers Squibb Pfizer Atrial Fibrillation Guidelines

A guidelines based approach to AF management • 67 year old male is scheduled for surgery • Pre-op consult regarding OAC management • Past history includes 2 years of auto-rate- controlled persistent AF, controlled HT, controlled type II diabetes, prior MI, NYHA class II CHF, no angina, otherwise well • On irbesartan / HCTZ 300 mg / 25 mg OD, insulin, warfarin (INR 2. 0 -3. 0) • Cannot take a beta blocker as heart rate slow www. ccs. ca Atrial Fibrillation Guidelines

A guidelines based approach to AF management • • HR 48 bpm, irreg/irreg; BP 150/85 mm Hg JVP 2 cm ASA, +ve HJR, S 4, II/VI MR murmur lungs clear, no pedal edema ECG: rate-controlled AF, old inferior MI L. Brent Mitchell CCS 2014 www. ccs. ca Atrial Fibrillation Guidelines

Peri-Procedure/Anticoagulation Management Recommendation We recommend that, in a patient with AF/AFL, a decision to interrupt antithrombotic therapy for an invasive procedure must balance the risks of a thromboembolic event (as indicated by a higher CHADS 2 score, mechanical heart valve, or rheumatic heart disease) with those of a bleeding event (as indicated by a higher HASBLED score and procedures with higher bleeding risk). (Strong Recommendation, Low Quality Evidence) Atrial Fibrillation Guidelines

A guidelines based approach to AF management • Stroke risk considerations: - CHADS 2 score = 3; CHA 2 DS 2 -VASc = 5 - no mechanical heart valve - no rheumatic heart disease • Bleeding risk considerations: - HASBLED score = 1 • No AT-Rx: stroke = 10. 5%/yr: major bleed = 3. 1%/yr • On warfarin: stroke = 3. 8%/yr: major bleed = 6. 7%/yr La. Haye SA et al: Eur J Cardiol 33: 2164 -71, 2012 (www. afib. ca) www. ccs. ca Atrial Fibrillation Guidelines

For peri-procedural bleeding risk, procedure matters: For this patient, preparing for a PPM implant, I would: 1. stop warfarin; no heparin bridging 2. stop warfarin; heparin bridging 3. continue warfarin www. ccs. ca Atrial Fibrillation Guidelines

For peri-procedural bleeding risk, procedure matters: For this patient, preparing for a PPM implant, I would: 1. stop warfarin; no heparin bridging 2. stop warfarin; heparin bridging 1. continue warfarin – Correct! the data to support that contention are provided by the trial BRUISE CONTROL given on the next slide www. ccs. ca Atrial Fibrillation Guidelines

A guidelines based approach to AF management BRUISE CONTROL: A RCT comparing continued warfarin versus discontinued warfarin with heparin bridging in patients undergoing PPM/ICD surgery. N = 681 significant hematoma p<0. 001 other AEs p=ns Birnie DH et al. N Engl J Med 368: 2084 -93, 2013 www. ccs. ca Atrial Fibrillation Guidelines

Peri-Procedure/Anticoagulation Management Recommendation • We suggest that interruption of anticoagulant therapy in a patient with AF/AFL is not necessary for most procedures with a very low risk of bleeding (Conditional Recommendation, Low Quality Evidence), including cardiac device implantation (pacemaker or implantable defibrillator) (Conditional Recommendation, High Quality Evidence) Other very low risk of bleeding procedures include most dental procedures, anterior chamber eye surgery, most dermatologic procedures. www. ccs. ca Atrial Fibrillation Guidelines

Patient has PPM implanted with ongoing warfarin therapy with no problems. One year later, requires a thoracotomy for removal of suspicious mass. For this patient preparing for a thoracotomy I would: 1. stop warfarin; no heparin bridging 2. stop warfarin; heparin bridging 3. continue warfarin www. ccs. ca Atrial Fibrillation Guidelines

Patient has PPM implanted with ongoing warfarin therapy with no problems. One year later, requires a thoracotomy for removal of suspicious mass. For this patient preparing for a thoracotomy I would: 1. stop warfarin; no heparin bridging 2. stop warfarin; heparin bridging – Correct! According to CCS AF Guidelines, this is the correct answer as this patient has a CHADS score of 3. Nevertheless, the evidence supporting a net benefit for heparin bridging is weak. Clinical trials of heparin bridging are underway. 3. continue warfarin www. ccs. ca Atrial Fibrillation Guidelines

Peri-Procedure/Anticoagulation Management - Recommendation We recommend that interruption of anticoagulant therapy in a patient with AF or AFL will be necessary for most procedures with an intermediate or high risk of major bleeding. (Strong Recommendation, Low Quality Evidence) When a decision to interrupt warfarin therapy for an invasive procedure has been made for a patient with AF/AFL, we suggest that bridging therapy with LMWH or UFH be instituted…in a patient at high risk of thromboembolic events (CHADS 2 ≥ 3, mechanical heart valve, stroke or TIA within 3 months, rheumatic heart disease). (Conditional Recommendation, Low Quality Evidence) www. ccs. ca Atrial Fibrillation Guidelines

A guidelines based approach to AF management In patients at high risk of thromboembolic events it is customary to use bridging LMWH or UFH heparin during warfarin withdrawal for an invasive procedure. The wisdom of this practice has been questioned by a meta -analysis of 33 observational trials and one RCT reporting that bridging therapy is associated with: – an increase in major bleeding (13. 1% vs 3. 4%, p<0. 0001) – no reduction in thromboembolic events (0. 9% vs 0. 6%) Ongoing RCTs – PERIOP-2 and BRIDGE Siegel D et al. Circulation 126: 1630 -9, 2012 www. ccs. ca Atrial Fibrillation Guidelines

Thoracotomy accomplished without complications after warfarin withdrawal and LMWH bridging. The lung mass turns out to be benign. Patient switched to apixaban 5 mg bid at his request. One year later planned for knee replacement. e. GFR = 85 ml/min/m 2 For this patient preparing for a new knee would: 1. stop apixaban 5 days; heparin bridging 2. stop apixaban 2 days; no heparin bridging 3. switch to warfarin then do as before www. ccs. ca Atrial Fibrillation Guidelines

Thoracotomy accomplished without complications after warfarin withdrawal and LMWH bridging. The lung mass turns out to be benign. Patient switched to apixaban 5 mg bid at his request. One year later planned for knee replacement. e. GFR = 85 ml/min/m 2 For this patient preparing for a new knee would: 1. stop apixaban 5 days; heparin bridging 2. stop apixaban 2 days; no heparin bridging - Correct! The half life of apixaban is sufficiently short and predictable that heparin bridging is not required unless the apixaban was stopped too early or the surgery was unexpectedly delayed. Nevertheless, neither of the other two answers is wrong, just unnecessary. 3. switch to warfarin then do as before www. ccs. ca Atrial Fibrillation Guidelines

A guidelines based approach to AF management Days of withdrawal prior to high bleeding risk procedure e. GFR ml/min/m 2 apixaban dabigatran rivaroxaban ≥ 80 2 -3 2 -3 50 - 80 2 -3 30 - 50 2 -3 4 2 -3 < 30* 2 -3 5 2 -3 2014 Focused Update CCS AF Guidelines Can J Cardiol (in press) www. ccs. ca Atrial Fibrillation Guidelines

Due to the rapid offset and onset kinetics of the current NOACs, bridging LMWH or UFH therapy is only required if the period of withdrawal is longer than that recommended. Assuming haemostasis, after the new knee I would: 1. restart apixaban 2. 5 mg bid on PO day 2 2. restart apixaban 5 mg bid on PO day 2 3. restart apixaban 5 mg daily on PO day 3 www. ccs. ca Atrial Fibrillation Guidelines

Due to the rapid offset and onset kinetics of the current NOACs, bridging LMWH or UFH therapy is only required if the period of withdrawal is longer than that recommended. Assuming haemostasis, after the new knee I would: 1. restart apixaban 2. 5 mg bid on PO day 2 2. restart apixaban 5 mg bid on PO day 2 3. restart apixaban 5 mg daily on PO day 3 – Correct! Knee replacement is intermediate risk of bleeding procedure. Recognizing that once a NOAC is started, anticoagulation is (at least transiently) obtained the same day, an optimal balance of risk of post-op bleeding versus risk of thromboembolic event suggests restarting the NOAC 72 hours after this surgery. www. ccs. ca Atrial Fibrillation Guidelines

Peri-Procedure/Anticoagulation Management Recommendation When apixaban, dabigatran, or rivaroxaban have been withdrawn for an invasive procedure we suggest that such therapy be restarted after the procedure one day after haemostasis is established (usually 48 hours for a procedure with a low risk of bleeding and 72 hours for a procedure with an intermediate or high risk of bleeding). (Conditional Recommendation, Low Quality Evidence) www. ccs. ca Atrial Fibrillation Guidelines

THANK YOU ! Please visit our website for more information www. ccs. ca Visit our Atrial Fibrillation Patient Guide www. heartandstroke. ca⁄AFguide www. ccs. ca Atrial Fibrillation Guidelines

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EXTRA SLIDES www. ccs. ca Atrial Fibrillation Guidelines

ATRIAL FIBRILLATION GUIDELINES ATRIAL FIBRILLATION GUIDELINES The Canadian Cardiovascular Society’s

About this Slide Set This slide set is a quick-reference tool that features essential diagnostic and treatment recommendations based on the 2010 CCS Atrial Fibrillation Guidelines, the 2012 CCS Atrial Fibrillation Guidelines Update and the 2014 Focused Update of the CCS guidelines for the management of AF. These recommendations are aimed to provide a reasonable and practical approach to care for specialists and allied health professionals obliged with the duty of bestowing optimal care to patients and families, and can be subject to change as scientific knowledge and technology advance and as practice patterns evolve. The guideline is not intended to be a substitute for physicians using their individual judgment in managing clinical care in consultation with the patient, with appropriate regard to all the individual circumstances of the patient, diagnostic and treatment options available and available resources. Adherence to these recommendations will not necessarily produce successful outcomes in every case. For the complete CCS Atrial Fibrillation Guidelines, or for additional resources, please visit our guidelines website at www. ccs. ca.

The 2014 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation Co-chairs and Authors Jeff S. Healey and Atul Verma Authors John A. Cairns, Stuart Connolly, Jafna L. Cox, Paul Dorian, David Gladstone, Gordon J. Gubitz, Noah Ivers, Kori Leblanc, Laurent Macle, Michael Sean Mc. Murtry, L. Brent Mitchell, Stanley Nattel, Pierre Pagé, Ratika Parkash, P. Timothy Pollak, Allan C. Skanes, Ian G. Stiell, Mario Talajic, Teresa S. M. Tsang and Carl Van Walraven. Publication date: October 2014

Baseline Evaluation for All Patients History and Physical Exam Establish Pattern (New Onset, Paroxysmal, Persistent or Permanent) • Establish Severity (including impact on quality of life) • Identify Etiology • Identify reversible causes (hyperthyroidism, ventricular pacing, supra-ventricular tachycardia, exercise, etc) • Identify risk factors whose treatment could reduce recurrent AF or improve overall prognosis (i. e. hypertension, sleep apnea, left ventricular dysfunction, etc) • Take social history to identify potential triggers (i. e. alcohol, intensive aerobic training, etc) • Elicit family history to identify potentially heritable causes of AF (particularly lone AF) • Determine thromboembolic risks • Determine bleeding risk to guide appropriate antiplatelet or antithrombotic therapy • Review prior pharmacologic therapy for AF, both for efficacy and adverse effects • Measure blood pressure and heart rate • Determine patient height and weight • Comprehensive precordial cardiac examination and assessment of jugular venous pressure, carotid and peripheral pulses to detect evidence of structural heart disease 12 -Lead Electrocardiogram • Document presence of AF • Assess for structural heart disease (myocardial infarction, ventricular hypertrophy, atrial enlargement, congenital heart disease) or electrical heart disease (ventricular pre-excitation, Brugada syndrome) • Identify risk factors for complications of therapy for AF (conduction disturbance, sinus node dysfunction or abnormal repolarization) • Document baseline PR, QT and QRS intervals. Echocardiogram • Document ventricular size, wall thickness and function • Evaluate left atrial size (if possible, left atrial volume) • Exclude significant valvular or congenital heart disease (particularly atrial septal defects) • Estimate ventricular filling pressures and pulmonary arterial pressure Other • Complete blood count • Coagulation profile • Renal function • Thyroid and liver function • Fasting lipid profile • Fasting glucose

Additional Investigations for Selected Patients Investigation Chest radiography Ambulatory electrocardiography (Holter monitor, event monitor, loop monitor) Treadmill exercise test Trans-esophageal echocardiography Electrophysiologic Study Serum calcium and magnesium Sleep Study (ambulatory oximetry or poly- Potential Role Exclude concomitant lung disease, heart failure, baseline in patients receiving amiodarone Document AF, exclude alternative diagnosis (atrial tachycardia, atrial flutter, AVNRT/AVRT, ventricular tachycardia), symptom-rhythm correlation, assess ventricular rate control Investigation of patients with symptoms of coronary artery disease, assessment of rate control Rule out left atrial appendage thrombus, facilitate cardioversion in patients not receiving oral anti-coagulation, more precise characterization of structural heart disease (mitral valve disease, atrial septal defects, cor triatum, etc) Patients with documented regular supra-ventricular tachycardia (i. e. atrial tachycardia, AVNRT/AVRT, atrial flutter) that is amenable to catheter ablation In cases of suspected deficiency (i. e. diuretic use, gastrointestinal losses) which could influence therapy (i. e. sotalol) In patients with symptoms of obstructive sleep apnea or in select patients with advanced symptomatic heart failure

Established Patterns and Severity of Atrial Fibrillation Patterns of Atrial Fibrillation SAF Score* SAF Score Newly Diagnosed AF Class 0 Paroxysm al: Selfterminating <7 d Persistent: Sustained ≥ 7 d Permanen t: Decision to continue in AF * Dorian P, Cvitkovic SS, Kerr CR; et al. Can J Cardiol. 2006; 22(5): 383 -386 Impact on QOL** Asymptomatic 1 Minimal effect on QOL 2 Minor effect on QOL 3 Moderate effect on QOL Severe effect on ** QOL = quality of QOL 4 life

Overview of AF Management AF Detected Assessment of Thromboembolic Risk (CHADS 2) Appropriate Antithrombotic Therapy Detection and Treatment of Precipitating Causes Management of Arrhythmia Rate Control Rhythm Control

Major Goals of AF/AFL Arrhythmia Management • Identify and treat underlying structural heart disease and other predisposing conditions • Relieve symptoms • Improve functional capacity/quality of life • Reduce morbidity/mortality associated with AF/AFL ✔ Prevent tachycardia-induced cardiomyopathy ✔ Reduce/prevent emergency room visits or hospitalizations secondary to AF/AFL • Prevent stroke or systemic thromboembolism Recommendations • We recommend that the goals of ventricular rate control should be to improve symptoms and clinical outcomes which are attributable to excessive ventricular rates. (Strong Recommendation, Low Quality Evidence) • We recommend that the goals of rhythm control therapy should be to improve patient symptoms and clinical outcomes, and that these do not necessarily imply the elimination of all AF. (Strong Recommendation, Moderate Quality Evidence)

Rate vs Rhythm Control for Patients with Symptomatic AF SYMPTOMATIC AF Special circumstances in which to consider early rhythm control: Highly symptomatic Multiple recurrences Extreme impairment in QOL Arrhythmia-induced cardiomyopathy ATTEMPT RATE CONTROL Beta-blocker Calcium channel blocker NO Pill in pocket antiarrhythmic therapy CONTINUE RATE CONTROL MODIFY RATE CONTROL - CONSIDER RHYTHM CONTROL Paroxysmal AF Low burden recurrence YES SYMPTOMS RESOLVE Persistent AF High burden recurrence Consider cardioversion Maintenance antiarrhythmic therapy Symptoms improve, don’t change improve, and patient in sinus but AF recurs maintains rhythm and sinus rhythm AF recurs Catheter ablation Observe. If AF recurs, determine if symptomatic

Rate Management Recommendations • We recommend that ventricular rate be assessed at rest in all patients with persistent and permanent AF or AFL (Strong Recommendation, Moderate Quality Evidence). • We recommend that heart rate during exercise be assessed in patients with persistent or permanent AF or AFL and associated exertional symptoms (Strong Recommendation, Moderate Quality Evidence). • We recommend that treatment for rate control of persistent or permanent AF or AFL should aim for a resting heart rate of <100 bpm (Strong Recommendation, High Quality Evidence). • We recommend beta-blockers or nondihydropyridine calcium channel blockers as initial therapy for rate control of AF or AFL in most patients without a past history of myocardial infarction or left ventricular dysfunction (Strong Recommendation, Moderate Quality Evidence). • We recommend beta-blockers as initial therapy for rate control of AF or AFL in patients with myocardial infarction or left ventricular systolic dysfunction (Strong Recommendation, High Quality Evidence). • We recommend AV junction ablation and implantation of a permanent pacemaker in symptomatic patients with uncontrolled ventricular rates during AF despite maximally tolerated combination pharmacologic therapy (Strong Recommendation, Moderate Quality Evidence). • We suggest that digoxin not be used as initial therapy for active patients and be reserved for rate control in patients who are sedentary or who have left ventricular systolic dysfunction. (Conditional Recommendation, Moderate Quality Evidence) • We suggest that digoxin be added to therapy with beta-blockers or calcium channel blockers in patients whose heart rate remains uncontrolled. (Conditional Recommendation, Moderate Quality Evidence) • We suggest that amiodarone for rate control should be reserved for exceptional cases in which other means are not feasible or are insufficient (Conditional Recommendation, Low Quality Evidence).

Overview of Rate Management Rate Control Drug Choices Heart Failure CAD No Heart Failure or CAD β-blockers ± Digoxin β-blockers* Calcium Channel Blockers# Combination Rx β-blockers* Calcium Channel Blockers# Digoxin† Combination Rx Drugs are listed in alphabetical order *β-blockers preferred in CAD # Non-dihydropyridine calcium channel blockers (diltiazem, verapamil) †Digoxin may be considered as monotherapy only in particularly sedentary individuals

Managing Rate Control - Recommended Drugs ß-Blockers Drug Dose Adverse Effects Atenolol 50 - 150 mg p. o. daily bradycardia, hypotension, fatigue, depression Bisoprolol 2. 5 - 10 mg p. o. daily as per atenolol Metoprolol 25 mg - 200 mg p. o. bid as per atenolol 20 - 160 mg p. o daily - bid as per atenolol 80 - 240 mg p. o. tid as per atenolol Nadolol Propranolo l Calcium Channel Blockers and Digoxin Drug Dose Adverse Effects Verapamil 120 - 480 mg p. o. daily 120 - 240 mg p. o. bid bradycardia, hypotension, constipation Diltiazem 120 - 480 mg p. o. daily 120 - 240 mg p. o. bid bradycardia, hypotension, ankle swelling 0. 0625 mg - 0. 25 mg p. o. daily bradycardia, nausea, vomiting, visual disturbance Digoxin

Rhythm Management Recommendations • We recommend the optimal treatment of precipitating or reversible predisposing conditions of AF prior to attempts to restore or maintain sinus rhythm (Strong Recommendation, Low Quality Evidence). • We recommend a rhythm-control strategy for patients with AF or AFL who remain symptomatic with rate-control therapy or in whom rate-control therapy is unlikely to control symptoms (Strong Recommendation, Moderate Quality Evidence). • We recommend that the goal of rhythm-control therapy should be improvement in patient symptoms and clinical outcomes, and not necessarily the elimination of all AF (Strong Recommendation, Moderate Quality Evidence). • We recommend use of maintenance oral antiarrhythmic therapy as first-line therapy for patients with recurrent AF in whom long-term rhythm control is desired (see Figures) (Strong Recommendation, Moderate Quality Evidence). • We recommend intermittent antiarrhythmic drug therapy (“pill in the pocket”) in symptomatic patients with infrequent, longer-lasting episodes of AF or AFL as an alternative to daily antiarrhythmic therapy (Strong Recommendation, Moderate Quality Evidence). • We recommend that oral antiarrhythmic drug therapy should be avoided in patients with AF or AFL and advanced sinus or AV nodal disease unless the patient has a pacemaker or implantable defibrillator (Strong Recommendation, Low Quality Evidence).

Rhythm Management Recommendations • We recommend that an AV blocking agent should be used in patients with AF or AFL being treated with a class I antiarrhythmic drug (eg, propafenone or flecainide) in the absence of advanced AV node disease (Strong Recommendation, Low Quality Evidence). • We recommend electrical or pharmacologic cardioversion for restoration of sinus rhythm in patients with AF or AFL who are selected for rhythm-control therapy and are unlikely to convert spontaneously (Strong Recommendation, Low Quality Evidence). • We recommend pre-treatment with antiarrhythmic drugs prior to electrical cardioversion in patients who have had AF recurrence post cardioversion without antiarrhythmic drug pre-treatment (Strong Recommendation, Moderate Quality Evidence). • We suggest that patients requiring pacing for the treatment of symptomatic bradycardia secondary to sinus node dysfunction, atrial or dual-chamber pacing be generally used for the prevention of AF (Conditional Recommendation, High Quality Evidence). • We suggest that, in patients with intact AV conduction, pacemakers be programmed to minimize ventricular pacing for prevention of AF (Conditional Recommendation, Moderate Quality Evidence).

Rhythm Management Recommendations • We recommend that dronedarone not be used in patients with permanent AF nor for the sole purpose of rate control (Strong Recommendation, High Quality Evidence). • We recommend dronedarone not be used in patients with a history of heart failure or a left ventricular ejection fraction < 40% (Strong Recommendation, Moderate Quality Evidence). • We suggest dronedarone be used with caution in patients taking digoxin (Conditional Recommendation, Moderate Quality Evidence). Practical Tip Dronedarone is a reasonable choice for rhythm control in selected patients with AF. Typically, these would be patients with nonpermanent (predominantly paroxysmal) AF with minimal structural heart disease. Consideration should be given to monitoring for liver enzyme elevations within 6 months of initiating therapy with dronedarone.

Overview of Rhythm Management Rhythm Control Choices Normal Systolic Function No Hx of CHF Dronedarone+ Flecainide* Propafenone* Sotalol# Rhythm Control Choices Hx of CHF or Left Ventricular Systolic Dysfunction EF > 35% EF ≤ 35% Amiodarone Sotalol** Amiodarone Catheter Ablation Drugs are listed in alphabetical order + Dronedarone should be used with caution in combination with digoxin • Class I agents should be AVOIDED in CAD and should be COMBINED with AV-nodal blocking agents # Sotalol should be used with caution in those at risk for torsades de pointes VT (e. g. female, age > 65 yr, taking diuretics) ** Sotalol should be used with caution with EF 35 -40% and those at risk for torsades de pointes VT (e. g. female, age > 65 yr, taking diuretics)

Managing Rhythm Control - Recommended Drugs Drug/D ose Flecainide 50 -150 mg BID Propafeno ne 150 -300 mg TID Amiodaro ne 100 -200 mg OD (after 10 g loading) Dronedaro ne 400 mg Effica cy 30 -50% 60 -70% 40% Toxicity Ventricular tachycardia Bradycardia Rapid ventricular response to AF or atrial flutter (1: 1 conduction) Abnormal taste Photosensitivity, Bradycardia, GI upset, Thyroid dysfunction, Hepatic toxicity, Neuropathy, Tremor, Pulmonary toxicity, Torsades de pointes (rare) GI upset Bradycardia Hepatic toxicity Comments Contraindicated in patients with CAD or LV dysfunction Should be combined with an AV nodal blocking agent Low risk of proarrhythmia Limited by systemic side effects Most side effects are dose & duration related Should not be used for rate control or for rhythm control in patients with a history of CHF or LV EF < 40%. Should be used with caution when added to digoxin.

Catheter Ablation Recommendations • We recommend catheter ablation of AF in patients who remain symptomatic following an adequate trial of antiarrhythmic drug therapy and in whom a rhythm control strategy remains desired. (Strong Recommendation, Moderate Quality Evidence). • We suggest catheter ablation to maintain sinus rhythm as first-line therapy for relief of symptoms in highly selected patients with symptomatic, paroxysmal atrial fibrillation. (Conditional Recommendation, Moderate Quality Evidence) • We recommend curative catheter ablation for symptomatic patients with typical atrial flutter as first line therapy or as a reasonable alternative to pharmacologic rhythm or rate control therapy (Strong Recommendation, Moderate Quality Evidence). • In patients with evidence of ventricular preexcitation during AF, we recommend catheter ablation of the accessory pathway, especially if AF is associated with rapid ventricular rates, syncope, or a pathway with a short refractory period (Strong Recommendation, Low Quality Evidence). • In young patients with lone, paroxysmal AF, we suggest an electrophysiological study to exclude a re-entrant tachycardia as a cause of AF; if present, we suggest curative ablation of the tachycardia (Conditional Recommendation, Very Low Quality Evidence).

Catheter Ablation Practical Tip AF ablation should not be considered as an alternative to oral anticoagulation. If a patient has a high thromboembolic risk profile, then the patient should continue oral anticoagulation even after successful AF ablation. Studies of long-term monitoring have consistently shown asymptomatic episodes of AF both prior to and following ablation. Initiation of oral anticoagulation should also not be delayed when indicated in patients pending referral for AF ablation. Practical Tip • The following represents a typical, but not exclusive, profile of a patient who is referred for consideration of AF ablation today: ü Age less than 80 ü Patients who are symptomatic with their AF ü Patients who have tried but failed or are intolerant of antiarrhythmic drug therapy ü Paroxysmal AF or short-standing persistent AF ü Minimal to moderate structural heart disease (such as LV dysfunction or valvular disease) Risk/Benefit Ratio for Ablation in Patients with Symptomatic AF Longstanding¶ Persistent Paroxysmal 1 st line -- -- + Failed 1 st drug -- + ++ Failed 2 nd drug Failed multiple drugs + ++ +++ +++ + Balance of risk and benefit in favor of catheter ablation ¶ Ongoing symptomatic AF ≥ 1 year

Prevention of Stroke in AF/AFL CHADS 2 Score Risk Factor CHA 2 DS 2 -VASc Score Risk Factor Score Congestive Heart Failure 1 Hypertension 1 Age ≥ 75 1 Age ≥ 75 2 Diabetes Mellitus 1 Diabetes Mellitus 1 Stroke/TIA/Thromboembolism Maximum Score 6 2 Vascular Disease 1 Age 65 -74 1 Female 1 Maximum Score 9 2

Prevention of Stroke in AF/AFL Recommendations • We recommend that all patients with AF or AFL (paroxysmal, persistent or permanent), should be stratified using a predictive index for stroke risk (for example, the “CCS algorithm” based on the CHADS 2 model). (Strong Recommendation, High Quality Evidence). • We recommend that OAC therapy be prescribed for most patients with age ≥ 65 years or CHADS 2 ≥ 1 (the “CCS algorithm”) (Strong Recommendation, Moderate Quality Evidence). • We recommend that when OAC-therapy is indicated for patients with non-valvular AF, most should receive dabigatran, rivaroxaban, apixaban or edoxaban (when approved) in preference to warfarin. (Strong Recommendation, High Quality Evidence). • We recommend that when OAC is indicated, warfarin be used rather than one of the NOACs for those patients with a mechanical prosthetic valve, those with rheumatic mitral stenosis and those with an Cr. Cl of 15 - 30 m. L/min (Strong Recommendation, Moderate Quality Evidence). • We recommend that patients whose risk of stoke warrants OAC therapy, but who refuse any OAC, should receive ASA 81 mg/ day plus clopidogrel 75 mg/ day (Strong Recommendation, High Quality Evidence). • We suggest that ASA (81 mg/day) be prescribed for patients with none of the risks outlined in the “CCS algorithm” (age < 65 years and no CHADS 2 risk factors) who have arterial vascular disease (coronary, aortic, or peripheral). (Conditional Recommendation, Moderate Quality Evidence) • We suggest no antithrombotic therapy for patients with none of the risks outlined in the “CCS algorithm” (age < 65 years and no CHADS 2 risk factors) and free of arterial vascular disease (coronary, aortic, peripheral). (Conditional Recommendation, Low Quality Evidence)

The “CCS Algorithm” for OAC Therapy in AF Age ≥ 65 YES OAC* NO Prior Stroke/TIA/SEor Hypertension or Heart failure or Diabetes Mellitus YES OAC* (CHADS 2 risk factors) NO CAD or Arterial vascular disease Consider and modify (if possible) all factors influencing risk of bleeding on OAC (hypertension, antiplatelet drugs, NSAIDSs, excessive alcohol, labile INRs) and specifically bleeding risks for NOACs (low Cr. Cl, age ≥ 75, low body weight)** ** may require lower dosing YES ASA (aortic, peripheral) NO No Antithrombotic * We suggest that a NOAC be used in preference to warfarin for non-valvular AF.

Prevention of Stroke in Patients with Chronic Kidney Disease (CKD) Recommendations • We recommend that patients with AF who are receiving OAC should have their renal function assessed at least annually by measuring serum creatinine and calculating Cr. Cl and should be regularly considered for the need for alteration of OAC drug and/or dose changes based on Cr. Cl (Strong Recommendation, Moderate Quality Evidence). For antithrombotic therapy of CKD patients, therapy should relate to Cr. Cl as follows: • Cr. Cl >30 m. L/min: We recommend that such patients receive antithrombotic therapy according to their risk as determined by the “CCS algorithm” as detailed in recommendations for patients with normal renal function (Strong Recommendation, High Quality Evidence). • Cr. Cl 15 -30 m. L/min and not on dialysis: We suggest that such patients receive antithrombotic therapy according to their risk as determined by the “CCS algorithm” as for patients with normal renal function. The preferred agent for these patients is warfarin (Conditional Recommendation, Low Quality Evidence). • Cr. Cl <15 m. L/min (on dialysis): We suggest that such patients not routinely receive either OAC or ASA for stroke prevention in AF (Conditional Recommendation, Low Quality Evidence).

Prevention of Stroke in Patients with Chronic Kidney Disease (CKD) – Therapeutic Choices in Patients with Chronic Kidney Disease and Stroke Risk Factors (CH GFR Warfarin Dabigatran Rivaroxaban Apixaban GFR ≥ 60 m. L/min Dose adjusted for INR 2. 0 -3. 0 150 mg bid or 110 mg bid 20 mg daily 5 mg bid† GFR 50 -59 m. L/min Dose adjusted for INR 2. 0 -3. 0 150 mg bid or 110 mg bid 20 mg daily 5 mg bid† GFR 30 -49 m. L/min Dose adjusted for INR 2. 0 -3. 0 150 mg bid or 110 mg bid 15 mg daily GFR 15 -29 m. L/min (not on dialysis) No RCT Data‡ No RCT Data§ No RCT Data¶ 5 mg bid Consider 2. 5 mg bid† 5 mg bid (for GFR > 25 m. L/min only) Consider 2. 5 mg bid† GFR < 15 m. L/min 2 No RCT Data‡ No RCT Data¶ No RCT Data † Consider Apixaban 2. 5 mg po bid if age ≥ 80 and body weight ≤ 60 kg. ‡ Dose adjusted warfarin has been used, but observational data regarding safety and efficacy is conflicting. (on dialysis) § Modelling studies suggest that dabigatran 75 mg bid might be safe for patients with GFR 15 -29 m. L/min, but this has not been validated in ¶ No published studies support a dose for this level of renal function; product monographs suggest the drug is contraindicated for this level o

Antithrombotic Management of AF/AFL in CAD - Recommendations • We suggest that patients with AF or AFL who have experienced ACS or who have undergone PCI, should receive antithrombotic therapy selected based on a balanced assessment of their risks of stroke, of recurrent coronary artery events and of hemorrhage associated with the use of combinations of antithrombotic therapies, which in patients at higher risk of stroke may include aspirin plus clopidogrel plus OAC. (Conditional Recommendation, Low Quality Evidence). Stable CAD Recent ACS PCI Choose antithrombotic based on stroke risk Choose antithrombotic based on balance of risks and benefits CHADS 2 = 0 CHADS 2 ≤ 1 CHADS 2 ≥ 2 ASA + clopidogrel + OAC ASA CHADS 2 ≥ 1 OAC

Management of AF in the ED Recommendations • For patients with no high-risk factors of stroke with cardioversion (recent stroke or TIA within 6 months; rheumatic heart disease; mechanical valve) and clear AF onset within 48 hours or therapeutic OAC therapy for ≥ 3 weeks, we recommend that they may undergo cardioversion in the ED without immediate initiation of anticoagulation. After attempted or successful cardioversion, antithrombotic therapy should be initiated as per the CCS algorithm (Strong Recommendation, Moderate-Quality Evidence) • For patients at high risk of stroke with cardioversion (not receiving therapeutic OAC therapy for ≥ 3 weeks with any of the following: AF episode duration not clearly < 48 hours, stroke or TIA within 6 months, rheumatic heart disease, mechanical valve), we recommend optimized rate control and therapeutic OAC for 3 weeks before and at least 4 weeks after cardioversion. (Strong • Recommendation, Moderate-Quality Evidence) We suggest that patients at high risk of stroke* during or after cardioversion may undergo cardioversion guided by transesophageal echocardiography. Anticoagulation should be initiated immediately using intravenous heparin or low molecular weight heparin prior to cardioversion. OAC therapy should then be initiated and maintained for at least 4 weeks post cardioversion. Patients should also be referred for early expert follow-up to review ongoing antithrombotic therapy, based upon stroke risk factors. (Conditional Recommendation, Moderate Quality • Evidence) We suggest that after conversion to sinus rhythm has been achieved, whether antiarrhythmic drug therapy is indicated should be based on the estimated probability of recurrence and the symptoms during AF. Long-term therapy will need to be determined by an appropriate outpatient consultation (Conditional Recommendation, Low Quality Evidence).

Management of AF in the ED – Recommendations YES Is Patient Stable? NO Immediate Risk for Stroke? Low Risk 1. Clear onset <48 hours, or 2. Therapeutic OAC ≥ 3 wks No therapeutic OAC ≥ 3 weeks High Risk** and one of: 1. Onset >48 hours or unknown, or 2. Stroke/TIA <6 months, or 3. Mechanical or rheumatic valve disease. Unstable – AF causing: 1. Hypotension, or 2. Cardiac ischemia, or 3. Pulmonary edema Rate-control Pharmacological or electrical CV at 150200 J (Immediate anticoagulation in ED before CV not required) Antithrombotic therapy Therapeutic OAC for 3 weeks before outpatient CV Antithrombotic therapy Trans-esophageal echocardiography (TEE) guided CV Consider urgent electrical CV if rate control not effective Antithrombotic therapy - Initiate immediate OAC* in ED -Initiate (or continue) OAC upon and continue for ≥ 4 weeks if ED discharge from ED if age ≥ 65 or - Continue OAC for ≥ 4 ‘high risk’ ** and continue for ≥ 4 weeks CHADS 2 ≥ 1 weeks after CV Early follow-up to review -Otherwise, initiate ASA if - Early follow-up to long-term OAC CAD/Vascular Disease review long-term OAC Emergency Management of AF -Early follow-up to review longterm OAC Immediate OAC = a dose of OAC should be given just prior to cardioversion – either a novel direct oral anticoagulant (NOAC) or a dose of heparin or low molecular weight heparin with bridging to warfarin if a NOAC is contraindicated.

Management of AF in the ED – Recommendations Recommended IV Drugs for Rate Control Drug Dose Risks Diltiazem* 0. 25 mg/kg IV bolus over 10 min; repeat at 0. 35 mg/kg IV Hypotension, bradycardia Metoprolol 2. 5 -5 mg IV bolus over 2 min; up to 3 doses Hypotension, bradycardia Verapamil* 0. 075 -0. 15 mg/kg over 2 min Hypotension, bradycardia Digoxin Bradycardia, Digitalis toxicity 0. 25 mg IV each 2 h; up to 1. 5 mg *Calcium-channel blockers should not be used in patients with heart failure or left ventricular dysfunction Recommended Drugs for Pharmacological Conversion Drug Class 1 A Procainamide Class IC* Propafenone Flecainide Class III Ibutilide Dose Efficacy Risks 15 -17 mg/kg IV over 60 min ++ 5% hypotension Hypotension, 1: 1 flutter, bradycardia 2 -3% Torsades de pointes 450 -600 mg PO +++ 300 -400 mg PO +++ 1 -2 mg IV over 10 -20 min ++ Pre-treat with Mg. SO 4 1 -2 gm *Class IC drugs should be used in combination with AV nodal blocking agents (beta-blockers or calcium-channel inhibitors). IV Class IC agents should also be avoided in patients with structural heart disease.

Peri-Procedure / Antithrombotic Management Recommendations • We recommend that in a patient with AF or atrial flutter, a decision to interrupt antithrombotic therapy for an invasive procedure must balance the risks of a thromboembolic event (as indicated by a higher CHADS 2 score, mechanical heart valve, or rheumatic heart disease) with those of a bleeding event (as indicated by a higher HASBLED score and procedures with higher bleeding risks) (Strong Recommendation, Low Quality Evidence). • We suggest that interruption of antithrombotic therapy in a patient with AF or AFL is not necessary for most procedures with a very low risk of bleeding and many procedures with a low risk of bleeding including cardiac device implantation (pacemaker or implantable defibrillator)(see Table) (Conditional Recommendation, Low Quality Evidence, High Quality Evidence for cardiac device implantation). • We recommend that interruption of antithrombotic therapy in a patient with AF or AFL will be necessary for most procedures with an intermediate or high risk of major bleeding (see Table) (Strong Recommendation, Low Quality Evidence).

Bleeding Risks for Various Invasive / Surgical Procedures High Risk Intermediat e Risk Low Risk • neurosurgery (intracranial • other • laparoscopic or spinal surgery) intraabdomin cholecystectomy • cardiac surgery (coronary al surgery • laparoscopic inguinal artery bypass or heart • other hernia repair valve replacement) intrathoracic • dental procedures • major vascular surgery • dermatologic (abdominal aortic • other procedures aneurysm repair, orthopedic • ophthalmologic aortofemoral bypass) surgery procedures* • major urologic surgery • other • coronary angiography (prostatectomy, bladder vascular • gastroscopy or tumour resection) surgery colonoscopy • major lower limb orthopedic • selected invasive surgery (hip/knee joint procedures (bone replacement surgery) marrow aspirate and • lung resection surgery biopsy, lymph node • intestinal anastomosis biopsy, thoracentesis, surgery paracentesis, • selected invasive arthrocentesis) procedures (kidney biopsy, • cardiac device prostate biopsy, cervical implantation surgery * Selected ophthalmic procedures may be high risk such as those with retrobulbar block cone biopsy, (pacemaker or **Based on results from BRUISE CONTROL trial (Birnie et al, N Engl J Med 2013; 368: 2084 -2093) pericardiocentesis, colonic implantable Very Low Risk • dental extractions (1 or 2 teeth) or teeth cleaning • skin biopsy or skin cancer removal • cataract removal

Pre-Procedure / Antithrombotic Management Recommendations • When a decision to interrupt aspirin or clopidogrel therapy for an invasive procedure has been made for a patient with AF or AFL, we suggest that the interruption begin 5 -7 days prior to the day of the procedure excepting those procedures with a very high risk of bleeding when we suggest that the interruption begin 7 -10 days prior to the procedure (Conditional Recommendation, Low Quality Evidence). • When a decision to interrupt warfarin therapy for an invasive procedure has been made for a patient with AF or AFL, we suggest that the interruption begin 5 days prior to the procedure and that a procedure with a low bleeding risk may proceed when the INR is <1. 5 and a procedure with an intermediate or high bleeding risk may proceed when the INR is <1. 2 (Conditional Recommendation, Low Quality Evidence). • We recommend that when LMWH or UFH bridging is used for an invasive procedure such therapy • When a decision to interrupt warfarin therapy for an invasive procedure has been made for a patient be started prior to the procedure when the INR is less than 2. 0 and be stopped 24 hours prior to with AF or AFL, we suggest that bridging therapy with LMWH or UFH be instituted when the INR is the procedure for LMWH and 4 -6 hours prior to the procedure for UFH (Strong recommendation, below that patient’s therapeutic INR target in a patient at high risk of thromboembolic events Low Quality Evidence) (CHADS 2 ≥ 3, mechanical heart valve, stroke or TIA within three months, rheumatic heart disease) • When a decision to interrupt apixaban or rivaroxaban therapy for an invasive procedure has been (Conditional Recommendation, Low Quality Evidence). made for a patient with AF or AFL, we suggest that the interruption begin 1 -2 days prior to the day of a procedure with a low risk of major bleeding and 2 -3 days prior to the day of a procedure with an intermediate or high risk of major bleeding (Conditional Recommendation, Low Quality Evidence). • When a decision to interrupt dabigatran therapy for an invasive procedure has been made for a patient with AF or AFL, we suggest that the interruption begin 1 -2 days prior to the day of a procedure with a low risk of major bleeding and 2 -3 days prior to the day of a procedure with an intermediate or high risk of major bleeding provided that the Cr. Cl is ≥ 80 m. L/min (Conditional Recommendation, Low Quality Evidence). The longer portion of these ranges should be used in patients with Cr. Cl 50 -80 m. L/min, an additional day should be added for patients with Cr. Cl 30 -50 m. L/min. In case the patient’s Cr. Cl is found to be <30 m. L/min, one more day of dabigatran

Post-Procedure / Antithrombotic Management Recommendations • When LMWH or UFH bridging is used for an invasive procedure, we suggest that such therapy be restarted after the procedure when hemostasis is established (usually 24 hours for a procedure with a low risk of bleeding and 48 -72 hours for a procedure with an intermediate or high risk of bleeding) in prophylactic dosages for the first 24 to 72 hours and then increased to therapeutic dosages. Bridging is then continued until an OAC is therapeutic (Conditional Recommendation, Low Quality Evidence). • When warfarin, ASA, or clopidogrel therapy has been interrupted for an invasive procedure, we suggest that such therapy be restarted after the procedure when hemostasis is established (usually 24 -48 hours for a procedure with a low risk of bleeding and 48 -72 hours for a procedure with an intermediate or high risk of bleeding) (Conditional Recommendation, Low Quality Evidence). • When apixaban, dabigatran, or rivaroxaban therapy has been withdrawn for an invasive procedure, we suggest that such therapy be restarted after the procedure one day after hemostasis is established (usually 48 hours for a procedure with a low risk of bleeding and 72 hours for a procedure with an intermediate or high risk of bleeding) (Conditional Recommendation, Low Quality Evidence).

Prevention and Treatment of AF following Cardiac Surgery Assess AF Risk Factors Low Risk High Risk On Beta. Blocker? No On Beta. Blocker? Yes No Yes Beta-Blocker Contraindicated ? Continue BB Beta-Blocker Contraindicated ? Sotalol or Amiodarone or BB plus IV Mg or Atrial Pacing No Yes Beta-Blocker Amiodarone Contraindicated ? Sotalol or Amiodarone or BB and IV Mg or Atrial Pacing Amiodarone Contraindicated ? No Yes Amiodarone IV Magnesium or Biatrial Pacing Amiodarone with or without IV Mg or Atrial Pacing IV Magnesium or Biatrial Pacing

Prophylactic Therapies for the Prevention of Post-Operative Atrial Tachyarrhythmias Therap y Pre-op beta blocker Pre-op amiodaro ne Post-op amiodaro ne Dosage* Cautions Adverse Effects any in usual therapeutic dose (i. e. metoprolol 50 mg) PO q 12 h or q 8 h for at least 2 pre-op days, day of surgery, and at least 6 post-op days reactive airways disease, decompensated CHF sinus bradycardia AV block hypotension bronchospasm 10 mg/kg/day (rounded to nearest 100 mg) divided into two daily PO dosages for 6 pre-op days, day of surgery, and 6 post-op days 30%-50% reduction in the dosages of other drugs with antiarrhythmic or sinus/AV nodal effects and warfarin will be required sinus bradycardia AV block hypotension torsade de pointes VT (rare) pulmonary toxicity (rare) 900 – 1200 mg IV over 24 hrs beginning within 6 hours of surgery, then 400 mg PO tid each of the next 4 days 30%-50% reduction in the dosages of other drugs with antiarrhythmic or sinus/AV nodal effects and warfarin will be required sinus bradycardia AV block hypotension torsade de pointes VT (rare) pulmonary toxicity (rare) hypotension (rare) sedation (very rare) renal failure respiratory depression (very rare) * Dosages used in the randomized studies vary widely and the optimal dosages for this indication have not been established. The dosages provided are those used in the largest positive trial of that therapy and are referenced to that study. Magnesiu m sulfate 1. 5 gm IV over 4 hrs first pre-op day, immediately post-op, and next 4 post-op days. Other trials have omitted the pre-op dosage