Atrial Fibrillation. E. Kevin Heist, MD, PhD. Updates in General Internal Medicine for Specialists January 28, 2019

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1 Atrial Fibrillation E. Kevin Heist, MD, PhD Updates in General Internal Medicine for Specialists January 28, 2019

2 Disclosures Abbott Consultant, Research Grant Biotronik Consultant Boston Scientific Consultant Medtronic Consultant Pfizer Consultant

3 Outline AF Mechanisms Rate vs. Rhythm Control Methods of Rhythm Control Pharmacologic Ablation Stroke Prevention Pharmacologic Devices

4

5 Atrial Fibrillation Mechanisms and Causes January et al, JACC 2014

6 Progression from Paroxysmal to Persistent AF ScienceMedia.com

7 Drug Therapy for Rate Control in AF Beta Blocker Therapy Calcium-Channel Blocker Therapy (Diltiazem, Verapamil) Digoxin (increased mortality in some studies) Amiodarone (useful in acutely ill patients, chronic use limited by drug toxicity)

8 Vamos et al, EHJ 2015;36: Digoxin Use and Overall Mortality

9 Digoxin Use and Overall Mortality AF Vamos et al, EHJ 2015;36:1831-8

10 Digoxin Use and Overall Mortality AF CHF Vamos et al, EHJ 2015;36:1831-8

11 RACE II: Intensity of Rate Control p=ns Lenient: resting hr < 110 (rest bpm achieved) Strict: resting hr < 80 hr mod exercise < 110 (rest bpm achieved) Primary Outcome: -cardiovascular death -CHF hospitalization -stroke -systemic embolism -bleeding -life threatening arrhythmia Van Gelder et al, NEJM 2010;362:

12 Electrical Cardioversion is effective, but Atrial fibrillation often recurs

13 Wyse et al, NEJM 2002;347: Medical Rate vs. Rhythm Control: AFFIRM

14 Observational Mortality Study of Rate vs. Rhythm Control in 26,130 Canadian Patients (66+ years old) Ionescu-Ittu et al, Arc Int Med 2012;172:

15 Drug Therapy: No Magic Pill

16 Rhythm Control: Amiodarone vs. Sotalol vs. Placebo Singh, BN et al, NEJM 2005;352:

17 January et al, JACC 2014 Antiarrhythmic Drug Therapy for AF

18 Drug Therapy for AF Summary Hard endpoints with AF rate control are as good as rhythm control (antiarrhythmic drugs) Beta blockers and calcium channel blockers are good rate control choices, digoxin may increase mortality Antiarrhythmic drugs for AF have moderate efficacy and potential for drug toxicity

19 Ablation Procedures for Atrial Fibrillation

20 Pulmonary Veins as Triggers of Paroxysmal Atrial Fibrillation Haissaguerre et al, NEJM 1998;339:659

21 Pulmonary Vein Isolation: Ablation for Paroxysmal AF

22 Catheter Ablation vs. Antiarrhythmic Drug Therapy for Paroxysmal AF *Protocol-Defined Treatment Failure: documented symptomatic atrial fibrillation Wilber et al, JAMA 2010;303:333-40

23 Balloon Ablation Catheters Cryothermy Ultrasound* Laser *investigational devices, not FDA approved

24 AF Ablation Methods: Cryoballoon vs RA Ablation: Fire and ICE Kuck et al, NEJM 2106;374:

25 January et al, JACC 2014 Lesion Sets in AF Ablation

26 Comparison of RF Ablation Approaches for Persistent AF: STAR-AF II Verma et al, NEJM;2015:372:

27 CABANA Study: AF ablation vs drug therapy Packer et al, HRS Late Breaking Trials, May 2018

28 CABANA Study: AF ablation vs drug therapy Packer et al, HRS Late Breaking Trials, May 2018

29 CABANA Study: AF ablation vs drug therapy Packer et al, HRS Late Breaking Trials, May 2018

30 AF and CHF Is There Benefit to AF Ablation?

31 PABA-CHF AF Ablation vs. AV Nodal Ablation/BiV Pacing Khan et al NEJM 2008;359:

32 CAMERA-MRI: AF Ablation vs Rate Control in CHF Patients (EF<45%) Prabhu et al, JACC 2017;70:

33 CASTLE-AF AF Ablation vs Medical Therapy in AF with CHF (EF<35%) Marrouche et al, NEJM 2018;378:417-27

34 CASTLE-AF AF Ablation vs Medical Therapy in AF with CHF (EF<35%) Marrouche et al, NEJM 2018;378:417-27

35 Surgical Approaches to AF LA RA Cannom AJC 2000;85:25D

36 FAST Study: Catheter or Surgical Ablation for AF Catheter Ablation: radiofrequency PVI (additional ablation lines at operator discretion) Surgical Ablation: VATS approach, radiofrequency PVI + LA ganglionated plexus ablation + LAA excision (additional ablation lines at operator discretion) Boersma et al, Circ 2012;125:23-30

37 FAST Study: Catheter or Surgical Ablation for AF Catheter Ablation: radiofrequency PVI (additional ablation lines at operator discretion) Surgical Ablation: VATS approach, radiofrequency PVI + LA ganglionated plexus ablation + LAA excision (additional ablation lines at operator discretion) Boersma et al, Circ 2012;125:23-30

38 Conclusion Regarding AF Ablation AF catheter ablation is more effective than antiarrhythmic drugs, but is not a guarantee of no AF Tools and strategies for AF ablation are evolving AF ablation may particularly benefit CHF patients Surgical AF ablation (Maze) appears more effective and more risky than catheter AF ablation

39 Stroke Prevention in Atrial Fibrillation

40 Larson, G, the Far Side Atrial Fibrillation and Warfarin Use

41 Stroke Is One of the Most Common and Devastating Complications of AF All-cause stroke rate with AF is 5% per year AF - independent risk factor for stroke ~5-fold increase in stroke risk ~15% of all strokes caused by AF Stroke risk increases with age Stroke risk persists in asymptomatic AF Fuster V, et al. Circulation. 2006;114:e257-e354. Wolf PA, et al. Stroke. 1991;22: Page RL, et al. Circulation. 2003;107: Hart RG, et al. J Am Coll Cardiol. 2000;35:

42 Stroke Risk Without Anticoagulation: CHADS 2 and CHADS 2 -VASc January et al, JACC 2014;64:e1-76.

43 Stroke Risk Without Anticoagulation: CHADS 2 -VASc

44 Preadmission Medications for Patients With Known AF Admitted with Stroke 597 high risk AF patients admitted with stroke in 12 stroke centers in Canada 2% Dual anti-platelet therapy No Antithrombotics 29% 29% Single antiplatelet therapy 10% Warfarin/subtherapeutic 29% Warfarin/ therapeutic Gladstone D, et al. Stroke. 2009;40:

45 ASSERT Study: stroke risk with pacemaker-detected atrial arrhythmias Atrial High Rate Episodes (AHRE) (> 6 min, > 190 bpm) found in 36% of pacemaker patients with no h/o AF AHRE increase risk of stroke/embolism by 2.5 fold 0.69%/year (no AHRE) 1.61%/year (+ AHRE) Healey et al, NEJM 2012;366:120-9

46 CRYSTAL AF Study Detection of AF in cryptogenic stroke 441 patients age > 40 with cryptogenic stroke No h/o AF and no AF on 24+ hour EKG monitor Randomized to implantable cardiac monitor or usual care Sanna et al, NEJM 2014;370:

47 Anticoagulation and Antiplatelet Therapy

48 Warfarin vs Placebo in Stroke Prevention in AF AFASAK-1 SPAF BAATAF CAFA SPINAF EAFT ALL Trials Warfarin reduces incidence of stroke by about 64% 100% 50% 0% -50% -100% Favors Warfarin Favors Placebo/ Control Hart R, et al. Ann Intern Med. 2007;146:

49 Aspirin vs Placebo in Stroke Prevention in AF AFASAK-1 SPAF I EAFT ESPS-II LASAF, daily LASAF, alternate day UK-TIA, 300 mg daily UK-TIA, 1200 mg daily JAST Aspirin Trials SAFT ESPS II, Dipyridamole ESPS II, Combination All Trials Antiplatelet therapy reduces incidence of stroke by about 22% Hart R, et al. Ann Intern Med. 2007;146: % 50% 0% -50% -100% Favors Antiplatelet Favors Placebo/ Control

50 Warfarin vs Antiplatelet Therapy in Stroke Prevention in AF AFASAK I AFASAK II Chinese ATAFS EAFT PATAF SPAF II, 75 yrs SPAF II, >75 yrs Aspirin trials SIFA ACTIVE-W NASPEAF All Trials 100% 50% 0% -50% -100% Favors Warfarin Favors Antiplatelet Hart R, et al. Ann Intern Med. 2007;146:

51 ACTIVE* W: Cumulative Risk of Stroke Cumulative Hazard Rates RR = 1.72 ( ), P = Number at risk Years Clopidogrel aspirin Oral anti coagulation therapy Primary outcome: stroke, systemic embolus, MI, vascular death. Connolly et al. Lancet. 2006;367: Clopidogrel + aspirin Oral anticoagulation therapy

52 Importance of Time within Therapeutic Range Patients Treated at Centers with TTR Below or Above 65% C+A: clopidogrel plus aspirin; OAC: oral anticoagulation therapy RR: relative risk of stroke C+A vs OAC Connolly S, et al. Circulation. 2008;118:

53 Warfarin Has a Narrow Therapeutic Window Relationship Between Clinical Events and INR Intensity in Patients with Atrial Fibrillation Odds Ratio Therapeutic Window Ischemic Stroke ICH INR Hylek EM, et al. Ann Intern Med. 1994;120: Hylek EM, et al. N Engl J Med. 1996;335:

54 Atrial Fibrillation Patients 55% of Their Time in Therapeutic INR Range Baker W, et al. J Manag Care Pharm. 2009;15:

55 Major Hemorrhage in First Year of Warfarin Therapy Prevalence of Major Hemorrhage Age > 80 Age < 80 9 intracranial bleeds 3 fatal 8/9 age > Days on Warfarin Hylek EM, et al. Circulation. 2007;115:

56 An Ideal Anticoagulant Desired Characteristic Rapid onset of action Wide therapeutic index Minimal side effects Oral formulation Predictable anticoagulant response No food or drug interaction Availability of antidote Cost effective Practical Advantage No need for overlap with heparin Increased safety Improved compliance; less monitoring Convenient administration Fixed-dose unmonitored treatment No need for monitoring Able to reverse in case of bleeding or urgent surgery Accessibility Sobieraj-Teague M, et al. Semin Thromb Hemost. 2009;35:

57 Emerging Therapies Factor Xa Inhibitors and Direct Thrombin Inhibitors Tissue Factor/VIIa X IX Idrabiotaparinux VIIIa Va Xa IXa Rivaroxaban* Betrixaban Apixaban* YM150 Edoxaban* *FDA Approved Drugs II IIa Dabigatran* AZD-0837 Fibrinogen Fibrin Harenberg J. Semin Thromb Hemost. 2009;35:

58 Apixaban AVERROES Atrial Fibrillation + 1 risk factor Failed or unsuitable for VKA therapy Screening Phase 0-28 days R N = 5,600 Apixaban 5 mg BID (Reduced to 2.5 mg/day for selected patients*) 1 and 3 months and every 3 months thereafter until study completion ASA (81 to 324 mg/day) *Patients with 2 of the following: Age 80 yrs Body weight 60 kg Serum creatinine 1.5 mg/dl or 133 μmol/l Primary efficacy outcome: stroke or systemic embolism Primary safety outcome: major bleeds Other outcomes: myocardial infarction, vascular death, all-cause death NCT Accessed Sept 2010.

59 Apixaban AVERROES Stroke or Systemic Embolic Event Cumulative Risk RR = % CI = P < Aspirin Apixaban Months No. at Risk ASA Apix Connolly S, et al. AVERROES.aspx. Accessed Sept 2010.

60 Apixaban AVERROES Outcome Apixaban (n = 2809) Aspirin (n = 2791) Relative Risk (95% CI) P value Stroke or systemic embolic event Stroke, embolic event, MI, or vascular death ( ) < ( ) < Major bleeding ( ) 0.56 Fatal bleeding ( ) 0.77 Intracranial bleeding ( ) 0.83 Connolly S, et al. AVERROES.aspx. Accessed Sept 2010.

61 Apixaban AVERROES Outcome Apixaban (n = 2809) Aspirin (n = 2791) Relative Risk (95% CI) P value Stroke or systemic embolic event Stroke, embolic event, MI, or vascular death ( ) < ( ) < Major bleeding ( ) 0.56 Fatal bleeding ( ) 0.77 Intracranial bleeding ( ) 0.83 Efficacy (stroke prevention): Eliquis superior to Aspirin Connolly S, et al. AVERROES.aspx. Accessed Sept 2010.

62 Apixaban AVERROES Outcome Apixaban (n = 2809) Aspirin (n = 2791) Relative Risk (95% CI) P value Stroke or systemic embolic event Stroke, embolic event, MI, or vascular death ( ) < ( ) < Major bleeding ( ) 0.56 Fatal bleeding ( ) 0.77 Intracranial bleeding ( ) 0.83 Safety (bleeding): Eliquis similar to Aspirin Connolly S, et al. AVERROES.aspx. Accessed Sept 2010.

63 ARISTOTLE Atrial Fibrillation with at Least One Additional Risk Factor for Stroke Inclusion risk factors Age 75 years Prior stroke, TIA, or SE HF or LVEF 40% Diabetes mellitus Hypertension Randomize double blind, double dummy (n = 18,201) Major exclusion criteria Mechanical prosthetic valve Severe renal insufficiency Need for aspirin plus thienopyridine Apixaban 5 mg oral twice daily (2.5 mg BID in selected patients) Warfarin (target INR 2-3) Warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device Primary outcome: stroke or systemic embolism Hierarchical testing: non-inferiority for primary outcome, superiority for primary outcome, major bleeding, death Granger et al, NEJM 2011;365:

64 ARISTOTLE: Primary Outcome Stroke (ischemic or hemorrhagic) or systemic embolism P (non-inferiority)< % RRR Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per year HR 0.79 (95% CI, ); P (superiority)=0.011 No. at Risk Apixaban Warfarin Granger et al, NEJM 2011;365:

65 ARISTOTLE: Major Bleeding (ISTH definition) 31% RRR Apixaban 327 patients, 2.13% per year Warfarin 462 patients, 3.09% per year HR 0.69 (95% CI, ); P<0.001 No. at Risk Apixaban Warfarin Granger et al, NEJM 2011;365:

66 Meta-Analysis: DOACs vs. Warfarin Dabig. Rivarox. Apix. Edox. Stroke or Systemic Embolism Dabig. Rivarox. Apix. Edox. Major Bleeding Ruff et al, Lancet 2014;383:955-62

67 DOACs vs Warfarin and All Cause Mortality Drug Dose Hazard Ratio (all cause death) Dabigatran* High Dose (150 mg bid) Low Dose* (110 mg bid) Rivaroxaban 20 or 15 mg daily Apixaban 5 or 2.5 mg bid P value (vs. warfarin) Edoxaban High Dose (60 or 30 mg daily) Low Dose (30 or 15 mg daily) *Dabigatran 110 mg is not an FDA approved dose for stroke prevention in AF

68 Idarucizumab (Praxbind) for reversal of dabigatran in patients with bleeding/urgent surgery on dabigatran Pollack et al, NEJM 2015;373: Dose: 5gm IV x1 FDA Approved: 10/16/2015

69 ANNEXA-4: Andexanet Alfa for reversal of Rivaroxaban and Apixaban in patients with bleeding within 18 hours of DOAC Rivaroxaban Reversal Apixaban Reversal Dose: Bolus + 2 hour infusion for patients with bleeding within 18 hours of DOAC FDA Approved: May 4, 2018 Connolly SJ et al. N Engl J Med 2016;375:

70 DOAC Reversal Agent in Development Ciraparantag* (PER977): (small molecule, binds to anticoagulants) Reversal agent for Direct Thrombin Inhibitors, Factor Xa inhibitors and LMWH *Investigational agent, not FDA approved for clinical use

71 Clinical Challenges With New Anticoagulants No validated tests to measure anticoagulation effect No established therapeutic range Antidotes in various stages of development Assessment of compliance more difficult than with vitamin K antagonists Potential for unknown long-term adverse events Balancing cost against efficacy Lack of head-to-head studies comparing new agents Paucity of data on special populations (ESRD, prior major bleeds, extreme elderly, etc)

72 Cost Effectiveness of DOACs vs Warfarin for AF Large meta-analysis of 23 trials, over 94,000 patients On balance, DOACs were more effective at stroke prevention vs. warfarin DOACs had lower intracranial bleeding than warfarin DOACs were generally cost effective vs. warfarin (accounting for all health care costs) Lopez-Lopez et al, BMJ 2017;359:j5058

73 Mechanical Approaches to Stroke Prevention: LAA Occlusion and Ligation

74 Left Atrial Appendage (LAA) Closure vs Warfarin for Prevention of Stroke in Patients with AF Control: warfarin INR Intervention: percutaneous closure of LAA 4 Year Efficacy Composite endpoint of stroke, cardiovascular death, and systemic embolism LAA Closure: 2.3%/year Warfarin: 3.8%/year 4 Year All Cause Mortality LAA Closure: 3.2%/year Warfarin: 4.8%/year Hazard Ratio 0.66, p=0.04 Reddy et al, Heart Rhythm Society Late Breaking Trials 2013

75 Other LAA Occlusion Devices Amulet Device (*Investigational in US) Lariat (LAA Snare) Singh et al, Heart Rhythm 2010;7:370-6.

76 Surgical ligation of the left atrial appendage Superior RAO Cardiac CT reveals the appendage communicates with the body of the LA via a narrow aperture.

77 Conclusions Rate control is non-inferior to rhythm control for asymptomatic patients Strict rate control does not have clear benefit over lenient control Antiarrhythmic drugs have moderate efficacy for AF with risks/side effects Catheter ablation is more effective than drug therapy for maintenance of sinus rhythm Surgical ablation appears to be more effective and more risky than catheter ablation Anticoagulation with warfarin is useful for stroke prevention in AF New anticoagulants have an expanding role in stroke prevention, but unresolved issues remain Left atrial appendage occlusion may offer a future alternative to drug therapy for stroke prevention

78 Questions?