1. What’s new in EP. Say no to drugs
What’s new in EP? Say no to drugs? Lionel Faitelson MD FACC FHRS Tucson Heart Group TMC Cardiovascular Symposium 2012

2. New devices for arrhythmias?
Anti-arrhythmic drugs: VT and VF Defibrillators ICDs; ablation Anti-arrhythmic drugs: SVT and AFL and AF Ablation Anti-heart failure drugs Biventricular pacemakers and ICDs Anticoagulant drugs in AF: NEW Alternatives to anticoagulant drugs NEW

3. AF: Managing the LA appendage
Relevance
Magnitude of AF issue
Risk scores and anticoagulant therapies
Surgical options
Percutaneous options
Lariat
Watchman
Amplatzer cardiac plug
Other

4. Atrial Fibrillation Update 2012
6.4 million
                                     
San Francisco 700,000
Philadelphia 1.5 million
(H.Weitz MD)
Miami 400,000
Los Angeles 3.8 million

5. Atrial Fibrillation Update 2035
11.4 million
                                     
Boston 600,000
Philadelphia 1.5 million
San Francisco 700,000
Chicago 2.8 million
Houston 2 million
Los Angeles 3.8 million

6. Atrial fibrillation treatment

7. March 2010: 1,980,000 hits March 2011: 2,550,000 hits
Atrial fibrillation
March 2010: 1,980,000 hits
March 2011: 2,550,000 hits
January 2012: 9,500,000 hits

8. AF: Public awareness
September 2012 is Atrial Fibrillation Awareness Month

9. How do we determine stroke risk ?
CHADS2 (Gage, et al.: JAMA 2001)
Congestive heart failure - 1pt
Hypertension - 1pt
Age > pt
Diabetes - 1pt
Stroke or TIA pts
0 points – low risk ( strokes per 100 patient years)
1-2 points – moderate risk ( strokes per 100 patient years)
> 3 points – high risk ( strokes per 100 patient years)

10. How do we determine stroke risk ?
CHADS2 (Gage, et al.: JAMA 2001)
Congestive heart failure - 1pt
Hypertension - 1pt
Age > pt
Diabetes - 1pt
Stroke or TIA pts
0 points – low risk ( strokes per 100 patient years)
1-2 points – moderate risk ( strokes per 100 patient years)
> 3 points – high risk ( strokes per 100 patient years)

11. Lip Y, et al. Chest 2010, 137(2):263

12. Lip Y, et al. Chest 2010, 137(2):263

13. CHADS2 vs. CHA2DS2VASc
CHADS2 score 0: 1.4% events
CHA2DS2-VASc score 0: 0 events
CHA2DS2-VASc score 1: 0.6% events
CHA2DS2-VASc score 2: 1.6 events

15. Non-Valvular Atrial Fibrillation Stroke Prevention Medical Rx
Warfarin Problematic
Narrow therapeutic window
Multiple drug-drug/drug-food interactions
Genetic variability
Long half-life
PCI issues – triple therapy
Compliance
Contraindications
Bleeding risks

16. Non-Valvular Atrial Fibrillation Warfarin Use in AF Patients by Age% 
Only 55% of AF patients with no contraindications have evidence of warfarin use in previous 3 months
Other studies cite warfarin use in AF patients from 17-50%
Elderly patients with increased absolute risk least likely to be taking warfarin
Contraindications 30-40%
Ann Int Med 131(12), 1999

17. Atrial fibrillation 2009 Target INR 2-3

18. Non-Valvular Atrial Fibrillation Adequacy of Anticoagulation in Clinic
Low INR <1.6
Efficacy  4-fold
Therapeutic INR 2-3
High INR >3.2 %
Bungard: Pharmacotherapy 20:1060, 2001

19. Non-Valvular Atrial Fibrillation Stroke Pathology
Major fatal bleed with age >75 = 3%/year (30% over 10 years)
Intracranial hemorrhage
%/100 patient-years
3% in INR >4.0
10% if INR >4.5
Brass. Stroke 28(12), 1997 VanWalraven: JAMA 288, 2002

20. Non-Valvular Atrial Fibrillation Stroke Pathology
Insufficient contraction of LAA leads to stagnant blood flow
Most likely culprit: embolization of LAA clot
90% of thrombus found in LAA
TEE-based risk factors
Enlarged LAA
Reduced inflow and outflow velocities
Spontaneous Echo contrast
Blackshear: Ann Thoracic Surg 61, 1996 Johnson: Eur J Cardiothoracic Surg 17, 2000 Fagan: Echocardiography 17, 2000

21. Warfarin Effective Reversible Inexpensive Slow onset of action
Regular monitoring
Food interraction
Medication interraction
Difficult titration-regular dose adjustments

22. Warfarin Effective Reversible Inexpensive Slow onset of action
Regular monitoring
Food interraction
Medication interraction
Difficult titration-regular dose adjustments

24. RELY Dabigatran 110 mg twice daily
Equal to warfarin in stroke prevention
Warfarin 1.69%/yr – dabigatran (110mg) 1.53%/yr
Less bleeding than warfarin
Warfarin 3.36%/year – dabigatran (110mg) 2.71%/yr
Dabigatran 150 mg twice daily
More effective than warfarin in stroke prevention
Dabigatran (150mg) 1.11%/yr
Equivalent bleeding to warfarin
less hemorrhagic stroke than warfarin

25. ACC AHA HRS Afib Focused Update (Dabigatran), March 2011
Non-inferior to warfarin re thromboembolism (afib)
Caution when CrCl < 30ml/min
Increased dabigatran levels with amiodarone, verapamil
Half life hours
No reversal re hemorrhage
dialysis
? shelf life once bottle opened (FDA alert March 30, 2011)
Tablets must stay in manufacturer’s container
Label: discard product 30 days after opening container
Coagulation testing ??? aPTT, dilute thrombin time

27. Dabigatran compared to control (warfarin, enoxaparin, placebo)
Increased absolute risk of MI or ACS 0.27%
Increased relative risk of MI or ACS 33%

28. As effective or better than warfarin
Rivaroxaban
Once daily
As effective or better than warfarin
Less hemorrhagic stroke than warfarin
Similar reduction in ischemic stroke
Less bleeding than warfarin
No routine lab testing
No reversal
Half life 5-9 hours
Coagulation testing: aPTT
Discontinuation : increased stroke

29. Apixaban Twice daily As effective or better than warfarin
Less hemorrhagic stroke than warfarin
Similar reduction in ischemic stroke
Less bleeding than warfarin
Lower overall mortality
No routine lab testing
No reversal
Half life 8-15 hours
Coagulation testing: PT, aPTT

30. New anticoagulants Short half life – less bleeding
Subtherapeutic if misses one or two doses
Lack of need for routine monitoring
No standard available test to asses if anticoagulated
Generally safer than warfarin
No antidote
??? Dabigatran
Cost of medication
Overall cost of care

31. How about Clopidogrel + Aspirin ?
N Engl J Med online publication March 31, 2009

32. How about Clopidogrel + Aspirin ?
stroke 3.4% per year
major bleed 1.27% per year
Aspirin + clopidogrel:
stroke 2.4% per year
major bleed 2.0% per year
Warfarin still first line
? Role of aspirin + clopidogrel
N Engl J Med online publication March 31, 2009

33. LAA: Focus of interest in AF
Anticoagulants contra-indicated in 14 – 44% AF patients
Stroke risk 2-5% even with therapeutic INR
LAA – 90% of thrombi in nonvalvular nonrheumatic AF
LAA volume 0.77 – cc
LAA variable anatomy – multimodality imaging
Luis, Roper et al; Cardiology Research and Practice 2012

34. LAA: Surgical options Excision with oversew or staples
Exclusion with clips or sutures
LAA Occlusion Study: success 45-72%
LAA Surgery: excision 73% > exclusion 23%
LAA Atriclip: EXCLUDE trial: 98% success
Current surgical practice

35. History of Suture Closure
1955
1949
1947
1985
2000
2011
Resection of the Left Auricular Appendix
A Prophylaxis for Recurrent Arterial Emboli
JOHN L. MADDEN, M.D.
Department of Surgery, Long Island College of Medicine, Kings County Hospital, Brooklyn , NY
Amputation of the Canine Atrial Appendages
Hellerstein, HK
SYSTEMIC EMBOLISM AND LEFT AURICULAR THROMBOSIS IN RELATION TO MITRAL VALVOTOMY BY
AND
J. R. BELCHER, M.S., F.R.C.S. Surgeon, London Chest Hospital; Assistant Thoracic Surgeon, the Middlesex Hospital
USE OF THE SURGICAL STAPLER TO OBLITERATE
THE LEFT ATRIAL APPENDAGE
Laurence H. Coffin, M.D., F.A.C.S., Burlington, VT
Appendage Obliteration to Reduce Stroke in Cardiac Surgical Patients with Atrial Fibrillation
Division of Cardiovascular Diseases, Mayo Clinic Jacksonville FL & Mayo Clinic, Rochester, MN
JL Blackshear, MD, JA Odell, FGRCS(Ed)
Ligation of the Left Atrial Appendage Using an Automatic Stapler
VJ DiSesa, S Tam, LH Cohn
Division of Cardiac Surgery, Brigham & Women’s Hospital, Boston, MA

37. LAA: Lariat Prospective study; 82 pts; 3 month FU
Indications: AF; warfarin intolerance or CI, or embolic event on warfarin
96% of pts with successful closure have closure at 1 month
Need epicardial and endocardial access (CABG, XRT, valve surgery, pericarditis)
Unsuitable if pericardial adhesions present
FDA and CE approved
Lee at al; Heart Rhythm 2011

38. Pre-Clinical Results Objective
Evaluate safety & effectiveness in canine model of percutaneous LAA closure with the LARIAT
N=26 canines
Attempts to Capture
1 attempt: 23/26 ( 88%)
2 attempt: 3/26 ( 12%)
Complete Acute Closure: 26/26 (100%)
7d Closure: /3 (100%)
30d Closure: /3 (100%)
90d Closure: /4 (100%)
Histological Examination (all)
Inflammatory response: /10 ( 0%)
Complete Endothelioization: 10/10 (100%)
Circ Cardiovasc Interv: June 2010

39. Clinical Results – PLACE I
Total Patients
N=13
AF History
Persistent 12 (92%)
Flutter ( 8%)
Age
Avg: 57.3; Hi 64, Low 43
Sex
M = 8 (62%)
Type Procedure
LAA w/ MVR (15%)
LAA w/ ablation 10 (77%)
Ablation w/ LAA 1 ( 8%)
Type Access
Median Sternotomy 2 (15%)
Minimally Invasive (15%)
Percutaneous (70%)
Intent to Treat
12/13 (92%)
Acute Closure
12/12 (100%)
Complications
1/13 (8%) non-serious (anatomic)
Procedural Times
Avg: 85.7 min; Median min
Heart Rhythm: 2011:8:

40. Closure Without Compromise
LAA Pre-procedure
30 day Post-procedure

42. PLACETM Procedure
Permanent Ligation Approximation Closure and Exclusion

43. PLACETM Procedure

44. Clinical Results – Confidence in Closure
In a single center, non randomized study(PLACE II)*, 85 patients underwent closure of their left atrial appendage using the LARIAT Suture Delivery Device and accessories. Patients were followed at 1 day, 30 days, 90 days and 1 year with transesophageal echocardiography to determine closure quality. The results were as follows:
Intent-to-Treat
85/89 (96%)
Adverse Events (defined as access related or device failure)
3/89 (3.3%)** Access 3/89 (3.3%) Device 0/89 (0.0%)
Closure (defined as < 1mm residual flow)
1 day 81/85 (95%) 30 day 81/85 (95%) 90 day 77/81 (95%)
1 year 65/66 (98%)
* PLACE II Clinical Study  -KBET/90/B/2008; Dec Jun Submitted for publication. ** All non-serious: 2 pericardial access related. 1 transseptal access related.

45. LAA: Watchman

46. WATCHMAN® LAA Closure Technology

48. LAA: Watchman PROTECT AF (RCT); 707 pts; 18 month FU
Indication: Permanent or Paroxysmal AF; CHADS >1; suitable for warfarin
Noninferiority of the intervention demonstrated
CE approved
Reddy et al; Circulation 2011

49. PROTECT AF Clinical Trial Design
Prospective, randomized study of WATCHMAN LAA Device vs long-term warfarin therapy
2:1 allocation ratio device to control
800 patients enrolled from Feb 2005 to Jun 2008
Device group (463)
Control group (244)
Roll-in group (93)
59 enrolling centers (U.S. & Europe)
Follow-up requirements
TEE follow-up at 45 days, 6 months and 1 year
Clinical follow-up biannually up to 5 years
Regular INR monitoring while taking warfarin
Enrollment continues in Continued Access Protocol (CAP Study)

50. Key Participation Criteria
Key inclusion criteria
Age 18 years or older
Documented non-valvular AF
Eligible for long-term warfarin therapy, and has no other conditions that would require long-term warfarin therapy
Calculated CHADS2 score 1
Key exclusion criteria
NYHA class IV congestive heart failure
ASD and/or atrial septal repair or closure device
Planned ablation procedure within 30 days of potential WATCHMAN Device implant
Symptomatic carotid disease
LVEF <30%
TEE criteria: suspected or known intracardiac thrombus (dense spontaneous Echo contract

51. PROTECT AF Trial Endpoints
Primary efficacy endpoint
All stroke: ischemic or hemorrhagic
Deficit with symptoms persisting more than 24 hours or
Symptoms less than 24 hours confirmed by CT or MRI
Cardiovascular and unexplained death: includes sudden death, MI, CVA, cardiac arrhythmia and heart failure
Systemic embolization
Primary safety endpoint
Device embolization requiring retrieval
Pericardial effusion requiring intervention
Cranial bleeds and gastrointestinal bleeds
Any bleed that requires 2uPRBC
Some events will be counted as both safety and efficacy endpoints

52. Event-free probability
Intent-to-Treat Primary Safety Results
Device
Control
Events Total Rate Events Total Rate RR Cohort (no.) pt-yr (95% CI) (no.) pt-yr (95% CI) (95% CI)
600 pt-yr (8.5, 15.3) (1.9, 7.2) (1.48, 6.43)
900 pt-yr (6.4, 11.3) (2.2, 6.7) (1.18, 4.13)
Randomization allocation (2 device:1 control)
Device
ITT cohort: patients analyzed based on their randomly assigned group (regardless of treatment received)
Event-free probability
Control
900 patient-year analysis
Days
244
143 51 11
463
261 87 19

53. Specific Safety Endpoint Events
Pericardial effusions – largest fraction of safety events in device group
Stroke events – most serious fraction of safety events in control group
Bleeding events were also frequent

54. Pericardial Effusions by Experience
Throughout PROTECT AF Trial, procedural modifications and training enhancements were implemented
Procedural events would be expected to decrease over time
Pericardial effusions within 7 days of the procedure are most relevant to the device performance
Site implant group (includes roll-in subjects)
Any procedure/ device related
Any serious
Any
No. % No. % No. %
Early patients (1-3) 13/ / /
Late patients (4) 27/ / /
Total 40/ / /

55. Effusions in Recent Implant Experience
Rates obtained in the CONTINUED ACCESS Study confirm that the lower rates are sustained
Any procedure/ device related
Any serious
Any
No. % No. % No. %
1/ / /88 1.1

56. Event-free probability
Intent-to-Treat Primary Efficacy Results
Device
Control
Posterior probabilities
Events Total Rate Events Total Rate RR Non- Superiority Cohort (no.) pt-yr (95% CI) (no.) pt-yr (95% CI) (95% CI) inferiority
pt-yr (2.6, 6.7) (3.0, 9.1) (0.39, 1.67)
pt-yr (2.1, 5.2) (2.8, 7.6) (0.37, 1.41)
Randomization allocation (2 device:1 control)
WATCHMAN
ITT cohort: patients analyzed based on their randomly assigned group (regardless of treatment received)
Event-free probability
Control
900 patient-year analysis
Days
244
147 52 12
463
270 92 22

57. Event-free probability
Intent-to-Treat Hemorrhagic Stroke
Device
Control
Posterior probabilities
Events Total Rate Events Total Rate RR Non- Superiority Cohort (no.) pt-yr (95% CI) (no.) pt-yr (95% CI) (95% CI) inferiority
pt-yr (0.0, 0.9) (0.5, 3.9) (0.00, 0.80)
> pt-yr (0.0, 0.6) (0.7, 3.7) (0.00, 0.45)
Randomization allocation (2 device:1 control)
Device
Control
ITT cohort: patients analyzed based on their randomly assigned group (regardless of treatment received)
Event-free probability
900 patient-year analysis
Days
244
147 53 12
463
275 95 23

58. Risk/Benefit Analysis
Intent-to-treat analysis
Primary endpoint (intent to treat) achieved
Other statistically significant endpoint findings
Noninferiority for the primary efficacy event rate – 32% lower in device group
Noninferiority for stroke rate – 26% lower in device group
Superiority for hemorrhagic stroke – 91% lower in device group
Noninferiority for mortality rate – 39% lower rate in device group
Increased rate of primary safety events for the device group relative to the control group
Most events in the device group were procedural effusions that decreased over the course of the study
87% of patients discontinued warfarin at 45 days
Death/disability conclusion

59. Risk / Benefit Analysis
Per-protocol analysis
Superiority for the primary efficacy event rate
Approximately 86% of patients in the device group were able to be successfully implanted and discontinue warfarin therapy
Study demonstrates the role of the left atrial appendage in the pathogenesis of stroke due to AF
Based on average age, patients will experience a 56% reduction in safety events

60. Summary
Long-term warfarin treatment of patients with AF has been found effective, but presents difficulties and risk
PROTECT AF trial was a randomized, controlled, statistically valid study to evaluate the WATCHMAN device compared to warfarin
In PROTECT AF, hemorrhagic stroke risk is significantly lower with the device.
When hemorrhage occurred, risk of death was markedly increased
In PROTECT AF, all cause stroke and all cause mortality risk are equivalent to that with warfarin
In PROTECT AF, there are early safety events, specifically pericardial effusion; these events have decreased over time

61. Conclusion
The WATCHMAN LAA Technology offers a safe and effective alternative to warfarin in patients with non-valvular atrial fibrillation at risk for stroke and who are eligible for warfarin therapy

62. LAA: Amplatzer Cardiac Plug
Different from Amplatzer Septal Occluder
Registry; 141 pts; 24 hour FU
Indication: Permanent/paroxysmal AF
Early experience: Stroke 2.1%, device embolization 1.4%, tamponade 3.5%
Clinical trial pending
CE 12/2008
Park et al; CCI 2011

63. LAA CLOSURE: Amplatzer Cardiac Plug
CE Marked December 2008
US IDE feasibility phase enrollment is completed: 45 patients, randomized 2:1
US IDE pivotal phase to commence 2012
Evaluate safety & efficacy of ACP vs. warfarin in AF patients
Prospective, randomized 2:1 (device : warfarin)
Estimated 400 to 2000 patients
Primary efficacy endpoint: stroke & peripheral ischemic events
Acute safety endpoint
Long-term safety endpoint: death and major bleeds
Park et al; Cath and CV Intervention 2011

64. LAA: Other devices Coherex Wave Crest PLAATO
self expanding nitinol with coils and anchors and PTFE covering toward LA; LAA plug
actively recruiting
PLAATO
self expanding nitinol cage with anchors and PTFE covering
2 prospective trials: 111 and 64 pts
FU 10 months to 5 years
TIA/CVA 2.2% - CVA 3.8%
no longer available for clinical use

65. Left Atrial Appendage Closure
Multiple indications
Multiple approaches
CE and FDA issues
Closure