1. Are the Data Supportive? Academic View
CRT 2012
Washington, DC, USA, Feb 4-7, 2012
CHALLENGES TO DEVICE INNOVATION: ATRIAL APPENDAGE CLOSURE DEVICES CASE STUDIES
3:14PM
4:00PM
Mitchell W. Krucoff, MD (Moderator) Robert S. Schwartz, MD (Moderator)
Empire Ballroom
Patient Selection: Are the Data Supportive? - Academic View
3:15PM
3:25PM
Horst Sievert, MD
Patient Selection: Are the Data Supportive? - Industry View
3:35PM
Keith D. Dawkins, MD
Patient Selection: FDA View
3:45PM
Andrew Farb, MD
Panel Discussion: Which Patients to Study Post-Market Versus Pre-Market?
Maurice Buchbinder, MD (Panelist) Kenneth J. Cavanaugh, PhD (Moderator) Keith D. Dawkins, MD (Panelist) Andrew Farb, MD (Panelist) Horst Sievert, MD (Panelist) Ashwani P. Sastry, MD (Panelist) Xu Yan, PhD (Panelist)
…….. min
Patient Selection:
Are the Data Supportive? Academic View
………………………
Horst Sievert,
Ilona Hofmann, Ann-Kathrin Ziegler
CardioVascular Center Frankfurt,
Frankfurt, Germany .

2. Horst Sievert, MD Consulting Fees: CSI Epitek Gore HLT Lifetech NDC
Recor

3. Consulting Fees:
Trireme
Veryan
Trivascular
My presentation will include off label discussions:
Not yet decided

4. Conflict of Interest Statement
Physician name
Company
Relationship
Horst Sievert
Abbott, Access Closure, AGA, Angiomed, Ardian, Arstasis, Atritech, Atrium, Avinger, Bard, Boston Scientific, Bridgepoint, Cardiac Dimensions, CardioKinetix, CardioMEMS, Coherex, Contego, CSI, EndoCross, EndoTex, Epitek, Evalve, ev3, FlowCardia, Gore, Guidant, InSeal Medical, Lumen Biomedical, HLT, Kensey Nash, Kyoto Medical, Lifetech, Lutonix, Medinol, Medtronic, NDC, NMT, OAS, Occlutech, Osprey, Ovalis, Pathway, PendraCare, Percardia, pfm Medical, Rox Medical, Sadra, Sorin, Spectranetics, SquareOne, Trireme, Trivascular, Velocimed, Veryan
Consulting fees,
Travel expenses,
Study honoraria
Cardiokinetix, Access Closure, Lumen Biomedical, Coherex
Stock options,
Stocks

5. Patient Selection: Are the Data Supportive?
What does that mean?
After more than 10 yrs of experience with LAA closure!
Does it mean
When is LAA closure indicated clinically?
Which patients should be enrolled into future clinical trials?

6. I can use the same slides to answer all these questions
In the US they may help to design future trials for the next decade
In the rest of the world (95.6% of the world population) they may help to define the clinical indication

7. Unfortunately it could happen ...
... that not all of the 95.6 % of the OUS population can afford the procedure
... that the US can not afford enough trials to achieve approval of the devices

8. Potential indications for LAA closure
Patients with non-valvular atrial fibrillation
Patients with valvular atrial fibrillation
Patients who can take anticoagulation
Patients who can not take anticoagulation

9. Valvular Afib, can take anticoagulation
That's what has been evaluated in the PROTECT AF trial

10. Protect AF (System for Embolic PROTECTion in Patients with Atrial Fibrillation)
Multicenter
Prospective randomized
WATCHMAN gen vs coumadin 2:1
Non-inferiority trial
800 pts
2011: patient-years
Holmes D, et al Lancet 2009

11. In- & Exclusion Major inclusion criteria Major exclusion criteria
Non valvular AF with Chads2 score ≥ 1
No contraindications to coumadin
No co-morbidities mandating chronic warfarin use other than AF
Major exclusion criteria
LAA thrombus
Large PFO with significant atrial septal aneurysm
Mobile aortic atheroma
Symptomatic carotid artery disease

12. Primary Efficacy Endpoint Freedom from Stroke, Death, Systemic Embolization
Trend towards better outcome after LAA closure
31% lower relative risk in WATCHMAN Group
WATCHMAN is non-inferior to Coumadin

13. All Stroke
P<0.05
Events/100 patient years
22%

14. Hemorrhagic Stroke
P<0.05
Events/100 patient years
75%

15. Mortality
P<0.05
Events/100 patient years
30%

16. What are the concerns? Patient selection Technical success Safety
30% had CHADS2 1 and could have been treated with aspirin
Technical success
Implantation success only 90.9%
Residual 45 days in 14%
Safety
Warfarin use was not optimal
PROTECT did not show superiority of LAA closure

17. What are the concerns? Patient selection Technical success Safety
30% had CHADS2 1 and could have been treated with aspirin
Technical success
Implantation success only 90.9%
Residual 45 days in 14%
Safety
Warfarin use was not optimal
PROTECT did not show superiority of LAA closure

18. When to anticoagulate is a moving target
When PROTECT AF was designed, it was recommended to consider anticoagulation in patients with CHADS2 1
During the trial the recommendations where changed to CHADS2 2
Nevertheless all trials with new anticoagulants included patients with CHADS2 1

19. When to anticoagulate is a moving target
In daily practice, many patients with CHADS2 1 (with low bleeding risks) are anticoagulated
Aspirin is now considered to be ineffective in atrial fibrillation
We now have CHA2DS2-VASc

20. What is CHA2DS2-VASc ? Same principle as CHADS2 But
Calculation of the annual stroke risk based on observed strokes in patients with atrial fibrillation
But
Including more risk factors into the calculation
Many more patients (7329 vs 1733)

21. CHA2DS2 -VASc CHADS2 Cardiac failure 1 1 Hypertension 1 1
Age >
Diabetes
Stroke
Vascular disease (MI, PAD,...)
Age
Female
Lip et al, Am J Med 2010, Camm et al, Eur Heart J 2010

22. Annual stroke risk according to CHA2DS2-VASc
Anticoagulation recommended in CHA2DS2-VASc ≥ 2

23. Most patients with atrial fibrillation have a CHA2DS2-VASc ≥2
Cardiac failure
Hypertension
Age >
Diabetes
Stroke
Vascular disease (MI, PAD,...) 1
Age
Female

24. So at least in retrospect it was appropriate to include patients with a lower CHADS2
Very simple!

25. But it is even simpler than that:
Sooner or later almost all patients will reach a CHADS2 of 2 (age, hypertension,...)
unless they die early
and it does not make sense to take anticoagulation for several years and then close the LAA
Anticoagulation does not work at all in clinical practice

26. What are the concerns? Patient selection Technical success Safety
30% had CHADS2 1 and could have been treated with aspirin
Technical success
Implantation success only 90.9%
Residual 45 days in 14%
Safety
Warfarin use was not optimal
PROTECT did not show superiority of LAA closure

27. Learning Curve Performance PROTECT AF vs CAP
p-value*
p-value±
Early
Late
Procedure Time
(Mean ± SD)
62 ± 34
67 ± 36
58 ± 33
50 ± 21
<0.001
Implant Success
485/542 (89.5%)
239/271
(88.2%)
246/271
(90.8%)
437/460
(95.0%)
0.001
45-day Warfarin Discontinuation Among Implanted
414/478
(86.6%)
194/235
(82.6%)
220/243
(90.5%)
352/371
(94.9%)
*From tests comparing the PROTECT AF cohort with CAP
±From tests for differences across three groups (early PROTECT AF, late PROTECT AF, and CAP)
Improvements seen over time in PROTECT AF
Shorter implant time, higher implant success rate, higher warfarin discontinuation rate
Trends confirmed in CAP 27 27

28. There is an important learning curve regarding performance!
So I am sure that in future trials the FDA will insist that only very well trained operators participate

29. Is the performance also device dependend?
Of course!!
Let's look at Watchman Gen 4:

30. Performance PROTECT AF vs Gen IV
CAP
p-value*
p-value±
Early
Late
Procedure Time
(Mean ± SD)
62 ± 34
67 ± 36
58 ± 33
50 ± 21
<0.001
Implant Success
485/542 (89.5%)
239/271
(88.2%)
246/271
(90.8%)
437/460
(95.0%)
0.001
45-day Warfarin Discontinuation Among Implanted
414/478
(86.6%)
194/235
(82.6%)
220/243
(90.5%)
352/371
(94.9%)
Gen 4
97 %
*From tests comparing the PROTECT AF cohort with CAP
±From tests for differences across three groups (early PROTECT AF, late PROTECT AF, and CAP)
Improvements seen over time in PROTECT AF
Shorter implant time, higher implant success rate, higher warfarin discontinuation rate
Trends confirmed in CAP 30 30

31. "Great, we will have a device which is even better"
"Unfortunately not!
It is just too complicated to bring it into the market!"

32. What are the concerns? Patient selection Technical success Safety
30% had CHADS2 1 and could have been treated with aspirin
Technical success
Implantation success only 90.9%
Residual 45 days in 14%
Safety
Warfarin use was not optimal
PROTECT did not show superiority of LAA closure

33. LAA Closure is an interventional procedure
Interventional (and surgical) procedures initially must have a higher risk than medical therapy
Advantages of interventional procedures can only be expected during FU

34. Safety Freedom from device embolization, pericardial effusion, severe bleeding
Days from Randomization
Event Free Probability
365
730
1095
0.70
0.80
0.90
1.00
244
212
155 53
Control
463
364
303
116
Watchman
Mostly stroke and bleeding
Mostly pericardial effusion without sequelae

35. Are the complications unavoidable or are they operator dependent?
Mainly operator dependent!

36. Learning Curve Safety Event Rates
PROTECT AF
CAP
p-value*
p-value±
Early
Late
Procedure/Device Related Safety Adverse Events within 7 Days
42/542
(7.7%)
27/271
(10.0%)
15/271
(5.5%)
17/460
(3.7%)
0.007
0.006
Serious Pericardial Effusions within 7 Days
27/542
(5.0%)
17/271
(6.3%)
10/271
10/460
(2.2%)
0.019
0.018
Procedure Related Stroke
5/542
(0.9%)
3/271
(1.1%)
2/271
(0.7%)
0/460
(0.0%)
0.039
Improvements seen over time for acute safety events
Fewer total procedure/device related events
Kar et al. TCT 2011 36 36

37. Learning Curve Safety Event Rates
PROTECT AF
CAP
p-value*
p-value±
Early
Late
Procedure/Device Related Safety Adverse Events within 7 Days
42/542
(7.7%)
27/271
(10.0%)
15/271
(5.5%)
17/460
(3.7%)
0.007
0.006
Serious Pericardial Effusions within 7 Days
27/542
(5.0%)
17/271
(6.3%)
10/271
10/460
(2.2%)
0.019
0.018
Procedure Related Stroke
5/542
(0.9%)
3/271
(1.1%)
2/271
(0.7%)
0/460
(0.0%)
0.039
Improvements seen over time for acute safety events
Fewer total procedure/device related events
Kar et al. TCT 2011 37 37

38. What if we would repeat PROTECT AF today with the experience we now have? Freedom from device embolization, pericardial effusion, severe bleeding
1.00
0.90
Event Free Probability
0.80
Watchman
Control
244
212
155 53
Control
0.70
463
364
303
116
Watchman
365
730
1095
Days from Randomization
Well done, we just saved 5 yrs and millions of $

39. There is also an important learning curve regarding safety!
So I am sure that in future trials the FDA will insist that only very well trained operators participate

40. Will new anticoagulants change the picture?
Not really!
Because there are no late complications of LAA closure

41. Dabigatran - Major Bleeding
Everybody is looking at this difference
Warfarin 
Dabigatran 150
Cumulative hazard rates
Dabigatran 110
Follow-up (yr)
No. at risk
6,015 5,835 5,640 4,510 2,872 1,349
6,076 5,839 5,638 4,557 2,928 1,366
6,022 5,801 5,600 4,474 2,797 1,269
Connolly SJ et al: NEJM 361:1139, 2009

43. What are the concerns? Patient selection Technical success Safety
30% had CHADS2 1 and could have been treated with aspirin
Technical success
Implantation success only 90.9%
Residual 45 days in 14%
Safety
Warfarin use was not optimal
PROTECT did not show superiority of LAA closure

44. Correct, warfarin was not used optimal in PROTECT AF
Why?

45. Because anticoagulation does not work
INR within therapeutic range
PROTECT AF
67 %
ARISTOTLE
62%
ROCKET AF
58%
RELY
64%
ACTIVE W
SPORTIF V
68%
SPORTIF III
66%

46. Warfarin Use in General Practice Discontinuation
40-64
65-69
Age
70-74
75-79
80-84
85 %
Years after starting treatment
Gallagher AM et al: J Thromb Haemost 6:1500, 2008

47. Dabigatran Permanent Discontinuation
Stopping rates
Warfarin
Follow-up (yr)
No. at risk
6,015 5,336 5,026 3,950 2,491 1,176
6,076 5,329 5,015 3,955 2,528 1,172
6,022 5,563 5,269 4,158 2,561 1,187
Connolly SJ et al: NEJM 361:1139, 2009

48. What are the concerns? Patient selection Technical success Safety
30% had CHADS2 1 and could have been treated with aspirin
Technical success
Implantation success only 90.9%
Residual 45 days in 14%
Safety
Warfarin use was not optimal
PROTECT did not show superiority of LAA closure

49. Because PROTECT AF was designed to show non-inferiority
Of course not
Because PROTECT AF was designed to show non-inferiority

50. Valvular Afib, can take anticoagulation
LAA closure is an alternative to anticoagulation
Based on the results of PROTECT AF and other trials with the Watchman device
We do not need further trials
(I know they will be done anyway)
Instead, we should concentrate on improvements of the devices

51. Valvular Afib, can not take anticoagulation
That's what has been evaluated in the ASAP trial

52. The ASAP Trial (=ASA Plavix Feasibility Study)
Similar protocol as PROTECT AF
Same inclusion/exclusion criteria
But anticoagulation contraindicated
Multicenter
Preliminary results of 127 patients

53. ASAP – Results Successful implantation in 118/127 pts (93%)
Periprocedural complications
Pericardial tamponade 1
Pericardiocentesis, no sequelae
Device embolization 2
Successful percutaneuos retrieval of the device
Pseudoaneurysm (groin) 1
Surgical repair, no sequelae
Mean follow up = 10.4 months
58 pts have been followed to one year

54. Valvular Afib, can not take anticoagulation
LAA closure is an alternative to anticoagulation
Based on the results of the ASAP registry
We do not need further trials
They will add minimal additional information
Instead, we should concentrate on further improvements of the devices

55. Non - Valvular Afib
I don't know yet, but
I'll be back

56. Thank you