Atrial Fibrillation and Stroke Integris Stroke Conference 2015

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1 Integris Cardiovascular Physicians Atrial Fibrillation and Stroke Integris Stroke Conference 2015 Sean M. Halleran, MD, FACC, FHRS Clinical Cardiac Electrophysiology

2 Disclosures Pfizer, Bristol Myers Squibb speaker bureau Eliquis Janssen speaker bureau Xarelto Medtronic faculty Atrial Fibrillation Masters Program

3 Atrial Fibrillation Most commonly occurring dysrhythmia currently affecting an estimated 2.2 million Americans current estimates suggest that the prevalence of AF will reach 4 million by 2030 and climb to 5.6 million by 2050

4 Atrial Fibrillation Lifetime risk for AF for men and women over age 40 = 25% In the 9 th decade of life 60%

5 Atrial Fibrillation Burden of healthcare costs - astronomical proportions , number of AF-related hospitalizations increased 190% In 2001, AF was responsible for 416,000 hospital discharges $6041 paid to Medicare beneficiaries for each hospitalization post-discharge costs including medications physician visits procedures (including echocardiograms and cardioversions), transportation and loss of work experienced by patients after diagnosis of AF

6 Atrial Fibrillation Disease/Epidemiologic Associations Hypertension/HTN heart disease Age CAD Valvular heart disease HCM Congenital heart disease Chronic lung dz Obesity Surgery Cardiac Non-cardiac Alcohol Hyperthyroidism Obstructive sleep apnea

7 Atrial Fibrillation - Symptoms Palpitations sudden pounding, fluttering or racing sensation in chest Shortness of breath especially intermittent or paroxysmal symptoms Dizziness or lightheadedness Chest discomfort ASYMPTOMATIC More common in elderly or inactive 21% of patients with AF

8 Atrial Fibrillation Classification of AF First diagnosis or documented AF may ultimately be paroxysmal, persistent or permanent Paroxysmal - < 7 d (usually < 24 h), self terminating Persistent - > 7 d or Permanent - > 1 year, decision to no longer attempt maintence of SR Long standing recurrent, persistent

9 Natural History - Atrial Fibrillation

10 Atrial Fibrillation - Treatment The single most important aspect of treatment of atrial fibrillation is prevention of STROKE A day of atrial fibrillation is a bad day; a stroke is a bad life

11 Atrial Fibrillation and Stroke 15-20% of all strokes are caused by AF Persons risk of stroke with AF is 5x greater Mortality with AF related stroke is 2x greater Stroke risk does NOT depend on symptoms OR frequency OR duration of atrial fibrilation Stroke risk is frequently NOT temporally related to AF events Estimated that 80% of strokes in patients with AF are preventable American Heart Association

12 Atrial Fibrillation and Stroke Increased Risk Factors for Stroke Hypertension Diabetes Female gender Age Age > 75 double risk factor Prior Stroke or mini-stroke (TIA) double risk factor Heart Failure Vascular Disease (coronary, carotid, peripheral) Hyperthyroidism Valvular Heart disease mitral stenosis (not MR), heart valve replacments mechanical >> bioprosthetic mitral >> aortic

13 Atrial Fibrillation - Treatment Prevention of thromboembolic complications (CVA) CHADS2 Score CHA 2 DS 2 VASc Score

14 CHADS2 CHADS2 CHF 1 Hypertension 1 Age > 75 1 Diabetes 1 Stroke/TIA 2 Score 0 = Aspirin Score 1 = ASA or OAC Score > 2 = OAC

15 CHA 2 DS 2 VASc Score CHA 2 DS 2 VASc CHF 1 Hypertension 1 Age > 75 2 Diabetes 1 Prior Stroke or TIA 2 Vascular disease 1 Coronary, carotid, peripheral Age Female gender 1 Age > 75 = OAC Stroke/TIA = OAC Female Sex + 1 risk or Male Sex + 2 risk = OAC

16 Prevention of thromboembolic complications (CVA) Typical agents oral anticoagulants Warfarin INR 2-3 typically with mitral stenosis Dabigitran (Pradaxa) Direct thrombin inhibitor Rivaroxaban(Xarelto) Oral factor Xa inhibitor Apixaban (Eliquis) Oral factor Xa inhibitor Edoxaban (Savaysa) Oral factor Xa inhibitor

17 Prevention of thromboembolic Typical agents Aspirin complications (CVA) 81 mg??? 325 mg (SPAF trial) European usage of ASA Clopidogrel? Active A and Active W trials Take home message aspirin and clopidogrel probably better than aspirin alone, worse than warfarin or novel oral anticoagulants

18 Prevention of Thromboembolic Complications AF - Dabigatran Dabigatran (Pradaxa) v. warfarin Direct thrombin inhibitor BID dosing RE-LY Trial, Connolly NEJM centers, 18,113 patients AF and at least 1 risk factor for CVA Warfarin to INR 2-3, Dabigatran 110 mg bid, Dabigatran 150 mg bid 2 year follow-up, annualized primary end-point Warfarin 1.69% Dabigatran 110 mg 1.53% (p<0.001 for NI) Dabigatran 150 mg 1.11% (p<0.001 for superiority)

19 Prevention of Thromboembolic Complications AF - Dabigatran RE-LY Trial

20 Prevention of Thromboembolic Complications AF- Rivaroxaban Rivaroxaban (Xarelto) v. warfarin Factor Xa inhibititor daily dosing ROCKET AF Trial AHA ,264 patients CHADS2 > 2 Rivaroxaban non-inferior to warfarin by ITT Superior while taking study drug (non-itt) Similar bleeding, less ICH, major bleeding

21 Primary Efficacy Outcome Stroke and non-cns Embolism Cumulative event rate (%) Event Rate Rivaroxaban Warfarin Warfarin Rivaroxaban HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: <0.001 Days from Randomization ROCKET AF Trial Event Rates are per 100 patient-years Based on Protocol Compliant on Treatment Population

22 Prevention of Thromboembolic Complications AF - Apixaban Apixaban (Eliquis) vs. warfarin Factor Xa inhibitor BID dosing ARISTOTLE Trial NEJM ,201 patients CHADS2 > 1 Superiority over warfarin for prevention of systemic embolization Superiority over warfarin for major bleeding

23 Granger CB, Alexander JH, McMurray JJV et al. Apixaban versus warfarin in patients with atrial fibrillation. N Eng J Med 2011

24 Prevention of Thromboembolic Complications AF - Edoxaban Edoxaban (Savaysa) v. warfarin Factor Xa inhibititor daily dosing ENGAGE AF- TIMI 48 NEJM ,105 patients CHADS2 > 2 High dose vs. low dose edoxaban vs. warfarin Non-inferior to warfarin for stroke, systemic embolism Lower bleeding, less CV death Higher stroke in pts CrCl > 95

25 Prevention of Thromboembolic Complications AF - Edoxaban

26 Atrial Fibrillation - Treatment 2 separate arms of treatment Protection Prevention of Stroke Symptoms Reduce frequency and duration of episodes Rate control Rhythm control

27 AF Rate control Beta-blockers - favored Calcium channel antagonists (nondihydropyridine) Some AAD (sotalol, dronederone, amiodarone) Digoxin? Pacemaker Used with concomitant sinus node dysfunction Common conundrum fast when in AF, slow when in SR Class I indication for permanent pacing to allow for medication of the fast

28 AF Rhythm control Pharmacologic rhythm control Indicated for symptomatic relief of AF Non-indications Desire to stop anticoagulation Reduce risk of stroke Choice based on Side effect profile Presence of structural heart disease HF Hypertension Underlying renal and hepatic function

29 AF Rhythm control Moderate potency AAD Flecainide, propafenone, dronederone, sotalol Higher potency AAD Amiodarone, dofetilide

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31 AFFIRM Trial In patients with CVA warfarin was stopped 57% of patients in the rhythm control arm 33% in the rate control arm

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33 AFFIRM Trial Take Home Message NOT that rhythm control is not worthwhile Asymptomatic patients prevention of stroke and rate control are reasonable Sinus rhythm is good; standard methods of maintaining NSR (anti-arrhythmic drugs) may not be good DO NOT stop anti-coagulation in patients because you (or they) think they are in normal rhythm

34 The AF Rhythm Control Conundrum Sinus rhythm appears to be associated with improved mortality Anti-arrhythmic medications that are designed to lead to SR have not been associated with improved mortality Is there something else that can lead to SR by using no or less medication?

35 Atrial Fibrillation Ablation R. pulmonary artery L. pulmonary artery L. auricle L. superior pulmonary vein L. atrium L. inferior pulmonary vein R. superior pulmonary vein R. inferior pulmonary vein Coronary sinus Netter F. Atlas of Human Anatomy. 1989;Plate 202.

36 Atrial Fibrillation Catheter Ablation Pulmonary Veins triggers for atrial fibrillation

37 LA/Pulmonary Vein Muscle Fibers

38 Left Atrium, Posterior Wall

39 Pulmonary Vein Potentials

40 Premature Atrial Contraction from Pulmonary Vein

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42 Intracardiac Ultrasound (ICE)

43 Left Atrial Mapping and Catheter Ablation Visualization: Intracardiac Ultrasound Tenting of the intra-atrial septum during transeptal catheterization Transeptal Access to LA AcuNav 10 Fr Phased Array Diagnostic Ultrasound Catheter (by Acuson)

44 Transseptal Puncture

45 Catheter Ablation AF Electroanatomic Mapping

46 Atrial Fibrillation Radiofrequency Spot Welding Catheter Ablation

47 Cryothermal Balloon Pulmonary Arctic Circle Vein Isolation

48 Cryothermal vs. Radiofrequency Ablation Cryothermal lesion Radiofrequency lesion Khairy Circulation 2003

49 Pulmonary Vein Isolation

50 Catheter ablation of AF Pulmonary vein isolation

51 Pulmonary Vein Isolation Pulmonary vein connected

52 Pulmonary Vein Isolation During Ablation PV disconnected, AF organizing

53 Pulmonary Vein Isolation and AF termination

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55 Post PV isolation

56 AF ablation outcomes Symptom relief of AF after catheter ablation has been clear

57 AF ablation outcomes Stroke risk reduction and mortality reduction unclear trials ongoing CABANA

58 Cryptogenic Stroke Cryptogenic Stroke 30-40% of ischemic strokes Pathophysiology heterogenous Cardioembolic LAA (AF), LV thrombus Atheroembolic Thrombophilia Inflammatory conditions Atrial septal disorders

59 Cryptogenic Stroke Work up ECG 24 hour ECG monitoring Carotid imaging (CTA or MRA) Lipid panel Echocardiogram Selected Thrombophilia testing (age < 55)

60 ASSERT Trial 2580 patients with PPM or ICD, no hx AF At 3 mos, 10% incidence of sub-clinical atrial arrhythmias Associated with increased risk AF HR 5.6 Stroke or systemic embolism HR 2.5 In pts with CVA, subclinical AF present in 51% Subclinical atrial fibrillation and the risk of stroke. Healey JS, et aln Engl J Med. 2012;366(2):120.

61 CRYSTAL - AF 441 pts with Cryptogenic CVA Implantable loop recorder vs. conventional monitoring for occult AF At 6 mos AF detection 8.9% in ILR group 1.4% in control group Median time to AF detection in ILR 6 mos 41 days Median time to AF detection in ILR 12 mos 84 days

62 CRYSTAL - AF

63 CRYSTAL - AF

64 CRYSTAL - AF

65 Implantable Loop Recorders

66 ILR for Occult AF First patient in Oklahoma with ILR for cryptogenic CVA after CRYSTAL-AF

67 EMBRACE Trial 572 pts with cryptogenic CVA/TIA 30 day event monitor vs. 24 h holter AF detection rate 16.1% in 30 day monitoring 3.2% in 24 hour monitoring Atrial fibrillation in patients with cryptogenic stroke. Gladstone D et aln Engl J Med. 2014;370(26):2467.

68 Bleeding Risk in AF patients Retrospective claims analysis of Medicare Advantage patients Of 48,260 pts with AF, 34% (16,409) experienced incident of bleeding Of 16,409 pts with bleeding 43% had repeat bleeding 30% experienced bleeding while on OAC at time of bleed S. Deitelzweig, Bleeding as an Outcome Among Patients With Nonvalvular Atrial Fibrillation in a Large Managed Care Population. Clinical Therapeutics e1

69 Bleeding Risk in AF patients Bleeding rates correlated to escalating CHADS2 score and HASBLED score CHADS2 Score > Major Bleeding Event Rate % per year S. Deitelzweig, Bleeding as an Outcome Among Patients With Nonvalvular Atrial Fibrillation in a Large Managed Care Population. Clinical Therapeutics e1

70 Bleeding Risk in AF patients HAS-BLED

71 AF Anticoagulation Conundrum What are options for patients with AF with both high and competing risks for thromboembolic complications and major bleeding?

72 Left Atrial Appendage 90% of left atrial thrombi located in LAA Inflammation and fibrosis seen in atria of pts with AF more intense in LAA

73 Left Atrial Appendage Treatment for AF and CVA Open surgical ligation or amputation of LAA Retrospective study 205 pts with MVR +/- LAA ligation Embolic events lower in pts with ligation 3% vs. 17% Potential limitation of surgical ligation Incomplete ligation 22% ACC/AHA recommendation for LAA amputation at time of MVR Role of left atrial appendage obliteration in stroke reduction in patients with mitral valve prosthesis: a transesophageal echocardiographic study. García-Fernández MA et al J Am Coll Cardiol. 2003;42(7):1253.

74 LAA -Treatment for AF and CVA Percutaneous LAA occlusion Watchman Device Expandable device delivered via transseptal approach to the LAA Nitonol cage with PTFE covering PROTECT-AF Lancet 2009 Non-inferiority trial 2:1 Watchman v. warfarin CHADS2>1 Primary efficacy stroke, systemic embolism, death Primary safety - major bleeding, pericardial effusion, procedure related stroke, and device embolization

75 LAA -Treatment for AF and CVA Percutaneous LAA occlusion Watchman LAA Occluder PROTECT-AF Trial Lancet 2009

76 LAA -Treatment for AF and CVA Percutaneous LAA occlusion Watchman PROTECT AF 18 mo f/u, similar event rates 3 events per 100 pt-years Watchman vs. 4.9 in warfarin At 2.3 years 3% event rates Watchman vs. 4.3% Safety endpoints 7.4 events per 100 pt-years Watchman vs. 4.4 in warfarin Most early 50% pericardial effusion requiring drainage Watchman currently pending FDA approval; CE Mark approval in Europe

77 LAA -Treatment for AF and CVA Percutaneous LAA occlusion LARIAT system Percutaneous device with FDA approval for soft tissue closure evaluated for safety and efficacy (not approved) for occlusion of LAA in pts who cannot take OAC and who are at high risk for stroke

78 LAA -Treatment for AF and CVA Percutaneous LAA occlusion Lariat System

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81 LARIAT Patient Selection NVAF, CHADS 2 2, or a CHA 2 DS 2 -VASc 3. Contraindication to OAC History of bleeding with high risk of recurrence Recurrent syncope and falls High-risk occupations (e.g. athletes, divers, martial arts instructors) Aneurysms at risk for rupture (intracranial, aortic) Fixed malignant hypertension Thrombocytopenia Dual antiplatelet therapy with increased HAS-BLED score

82 LARIAT - System Contraindications previous cardiac surgery pericarditis, chest radiation Active LAA thrombus Cardiac CT to assess the anatomy of the LAA for suitability of the LARIAT system anatomic contraindications LAA located behind the pulmonary artery with superior orientation measure > 40 mm.

83 Thank You