1. CRT 2017: Putting LAA closure in the age of DOACs into perspective
Stefan Bertog, Laura Vaskelyte, Markus Reinartz, Ilona Hofmann, Predrag Matic, Bojan Jovanovic, Kolja Sievert, Horst Sievert
Cardiovascular Center Frankfurt

2. Disclosure Statement of Financial Interest
I, Stefan Bertog, DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation.

3. Case 1 CHADS2VASC 4 (4.8% annual stroke) HASBLED 8.9
76 yo male with atrial fibrillation
Referred for LAA closure because high stroke and bleeding risk
PMH:
Parkinson
HTN
Stable coronary artery disease
History of GI bleeding requiring transfusion (diverticulosis)
History of intracranial hemorrhage from a fall while on warfarin
CHADS2VASC 4 (4.8% annual stroke)
HASBLED 8.9

4. Case 1 Perspective in the age of DOACs?
No data to show that DOACs are safe
Multiple non-randomized studies demonstrating safety and efficacy with LAAC
Hence, in the absence of other alternatives, LAAC should be considered
Boersma at al. EHJ 2016;37:
Reddy et al. 2013;61:
Renou et al. in press Journal of Stroke and Cerebrovascular Disease 2017

5. Case 2 CHADS2VASC 5 (6.7% annual stroke) HASBLED 1.9-4.1
76 yo female with atrial fibrillation
Referred for LAA closure because of patient’s stated fear of bleeding on anticoagulation
PMH:
HTN
Stable coronary artery disease (stents 4 yrs ago)
CHADS2VASC 5 (6.7% annual stroke)
HASBLED

6. Case example
Patient informed by referring provider that major bleeding risk with LAA closure is much lower than with anticoagulation

7. Case example Major bleeding:
What does current randomized trial data comparing warfarin to LAA closure show?

8. All major bleeding A. B. C. D.
Favors Warfarin 1
Favors Watchman

9. P=0.97 Watchman All major bleeding
Holmes et al. Am Coll Cardiol 2015;65:2614–23
Price et al. J Am Coll Cardiol Intv 2015;8:1925–32

10. Watchman P=0.97 Watchman All major bleeding
Holmes et al. Am Coll Cardiol 2015;65:2614–23
Price et al. J Am Coll Cardiol Intv 2015;8:1925–32

11. Case example
What should we tell the patient regarding the bleeding risk with warfarin versus LAA closure?

12. Case example
Your risk of suffering from major bleeding is no lower with LAA closure than with warfarin
If you live longer than 5 years eventually your major bleeding risk may be lower with LAA but this is an assumption
Price et al. J Am Coll Cardiol Intv 2015;8:1925–32

13. Case example
Your risk of suffering from major bleeding is no lower with LAA closure than with warfarin
If you live longer than 5 years eventually your major bleeding risk may be lower with LAA but this is an assumption
If you find an operator who can do the procedure with a < 3% pericardial hemorrhage rate then your major bleeding risk at 5 years or earlier may be lower, but this is an assumption
Tzikas et al. EuroIntervention 2015;10
Reddy et al. JACC VOL . 69, NO. 3, 2017 3%
The pericardial effusion rate was 4% in PROTECT AF (1.6% required surgery and 2.4% pericardiocentesis). It was 1.9% in PREVAIL (1.5% required pericardiocentesis and 0.4% surgery). The total pericardial effusion rate requiring either pericardiocentesis or surgery was 3% (taking both PROTECT AF and PREVAIL into account).
Price et al. J Am Coll Cardiol Intv 2015;8:1925–32

14. Case example
Your risk of suffering from major bleeding is no lower with LAA closure than with warfarin
If you live longer than 5 years eventually your major bleeding risk may be lower with LAA but this is an assumption
If you find an operator who can do the procedure with a < 3% pericardial hemorrhage rate then your major bleeding risk at 5 years or earlier may be lower, but this is an assumption
The pericardial effusion rate was 4% in PROTECT AF (1.6% required surgery and 2.4% pericardiocentesis). It was 1.9% in PREVAIL (1.5% required pericardiocentesis and 0.4% surgery). The total pericardial effusion rate requiring either pericardiocentesis or surgery was 3% (taking both PROTECT AF and PREVAIL into account).
Price et al. J Am Coll Cardiol Intv 2015;8:1925–32

15. Case example
Your risk of suffering from major bleeding is no lower with LAAC than with warfarin
If you live longer than 5 years, eventually, your major bleeding risk may be lower with LAAC but this is an assumption
If you find an operator who can do the procedure with a < 3% pericardial hemorrhage rate then your major bleeding risk at 5 years or earlier may be lower, but this is an assumption
What about the risk of major bleeding with DOACs compared with warfarin?
The pericardial effusion rate was 4% in PROTECT AF (1.6% required surgery and 2.4% pericardiocentesis). It was 1.9% in PREVAIL (1.5% required pericardiocentesis and 0.4% surgery). The total pericardial effusion rate requiring either pericardiocentesis or surgery was 3% (taking both PROTECT AF and PREVAIL into account).

16. DOAC
All major bleeding
Ruff et al. Lancet, 383:955 (2014)

17. DOAC
All major bleeding
Ruff et al. Lancet, 383:955 (2014)

18. DOAC
All major bleeding
Ruff et al. Lancet, 383:955 (2014)

19. Case example
If you are at low bleeding risk but major bleeding is your main concern, data currently would favor certain DOACs over warfarin and LAAC
What about stroke protection with LAAC versus warfarin?

20. All stroke or systemic embolism
Watchman
All stroke or systemic embolism
Holmes et al. Am Coll Cardiol 2015;65:2614–23

21. Case example
What can we tell the patient regarding the stroke risk with warfarin versus LAA closure?
The all stroke/systemic embolism rate is the same with warfarin compared with LAA closure
What about the stroke/systemic embolism rate with DOACs compared to warfarin?

22. Stroke or systemic embolism
DOAC
Stroke or systemic embolism
Ruff et al. Lancet, 383:955 (2014)

23. Case example Disabling strokes? LAA closure versus warfarin
Reddy et al. JAMA. 2014;312(19):

24. DOAC and strokes
Connolly et al. N Engl J Med 2009;361:

25. DOAC and strokes
Giugliano et al. Stroke. 2014;45:

26. Case example
Will I live any longer if I undergo LAA closure versus anticoagulation with warfarin?

27. Watchman
All cause death
Holmes et al. Am Coll Cardiol 2015;65:2614–23

28. DOAC
All cause mortality
Ruff et al. Lancet, 383:955 (2014)

29. Case 2 conclusion:
Whereas LAAC is equivalent to warfarin in stroke prevention in patients who are not at high bleeding risk, some DOACs appear to be more effective than warfarin and should remain the first choice
If, with newer generation LAA closure devices and more implant experience, the procedural risk can be improved, the risk/benefit ratio may favor LAA closure to warfarin even in patients at low bleeding risk

30. The safety of DOACS and warfarin is not likely to change However….
LAAC experience and technology will continue to improve

31. The analysis of 3822 consecutive cases in the US
Reddy et al. JACC VOL . 69 , NO.3, 2017

32. Your risk of suffering from major bleeding is no lower with LAA closure than with warfarin
If you live longer than 5 years eventually your major bleeding risk may be lower with LAA but this is an assumption
If you find an operator who can do the procedure with a < 3% pericardial hemorrhage rate then your major bleeding risk at 5 years or earlier may be lower, but this is an assumption 3%
The pericardial effusion rate was 4% in PROTECT AF (1.6% required surgery and 2.4% pericardiocentesis). It was 1.9% in PREVAIL (1.5% required pericardiocentesis and 0.4% surgery). The total pericardial effusion rate requiring either pericardiocentesis or surgery was 3% (taking both PROTECT AF and PREVAIL into account).

33. Case example
Your risk of suffering from major bleeding is no lower with LAA closure than with warfarin
If you live longer than 5 years eventually your major bleeding risk may be lower with LAA but this is an assumption
If you find an operator who can do the procedure with a < 3% pericardial hemorrhage rate then your major bleeding risk at 5 years or earlier may be lower, but this is an assumption
The pericardial effusion rate was 4% in PROTECT AF (1.6% required surgery and 2.4% pericardiocentesis). It was 1.9% in PREVAIL (1.5% required pericardiocentesis and 0.4% surgery). The total pericardial effusion rate requiring either pericardiocentesis or surgery was 3% (taking both PROTECT AF and PREVAIL into account).

36. Apixaban
Major bleeding
Ruff et al. Lancet, 383:955 (2014)

37. Stroke and systemic embolism
Apixaban
Stroke and systemic embolism
Ruff et al. Lancet, 383:955 (2014)

38. Apixaban All cause mortality
Granger et al. N Engl J Med 2011;365:981-92

39. Warfarin
Apixaban
Watchman
All stroke/systemic embolism
ICH
All cause death
All major bleeding

40. Case 1 Perspective in the presence of DOACs:
No studies addressing the safety of DOACs in patients considered at high bleeding risk or prior intracranial hemorrhage
What about left atrial appendage closure?
No randomized trials assessing safety and efficacy of LAA closure in patients at high bleeding risk or risk of ICH

41. Case 1
ASAP study
150 patients considered to have contraindications to oral anticoagulation
Mean CHADS2VASC 4.4
LAAC with the Watchman device
ASA indefinitely and clopidogrel for 6 months
Mean follow-up 16.5 months
Observed ischemic stroke rate was 1.5% (the overall stroke rate was 2.3%). In red is the expected stroke rate based on CHADS2 score (this was 2.8). In terms of safety, there were 2 pericardial effusions requiring percutaneous drainage (1.3%) and 6 (4%) device-associated thrombi only one of which was associated with a stroke. There were two embolizations that were managed percutaneously. Median time of device thrombus 165 days
Reddy et al. 2013;61:

42. Case 1 1021 patients who underwent Watchman implantation
27% on AC, 59% dual antiplatelet, 7% on single, 6% without any therapy
62% were deemed anticoagulant therapy ineligible, successful deployment: 98.5%, pericardial effusion requiring drainage in 3 (0.3%), procedure related stroke (1, 0.1%), major bleeding requiring transfusion in 17 patients, 8 were procedure related (groin complications) and 4 GI hemorrhage. In these 17 patients three were anticoagulated, single AP in five, DAPT in 7 and 2 without AC.
Periprocedural events captured
Boersma at al. EHJ 2016;37:

43. 738 patients did not undergo anticoagulant therapy after implant
Case 1
Overall event rate low
738 patients did not undergo anticoagulant therapy after implant
62% were deemed anticoagulant therapy ineligible, successful deployment: 98.5%, pericardial effusion requiring drainage in 3 (0.3%), procedure related stroke (1, 0.1%), major bleeding requiring transfusion in 17 patients, 8 were procedure related (groin complications) and 4 GI hemorrhage. In these 17 patients three were anticoagulated, single AP in five, DAPT in 7 and 2 without AC.
Serious adverse event rates at 30 days demonstrates that it was at least as safe if not safer not being anticoagulated.
There were 3 ischemic strokes that occurred within 30 days (two had a complete recovery), they occurred on day and 23. Two were on double antiplatelet therapy, one on single antiplatelet therapy
Boersma at al. EHJ 2016;37:

44. Case 1 How about safety of LAAC in patients with previous ICH?
No routine TEE follow-up but 82% had CT follow-up with one device-associated thrombus that resolved after 6 months of dual AP therapy
46 patients with prior ICH, ACP in 40, Watchman in 6.
All patients received aspirin only postprocedure
Renou et al. in press Journal of Stroke and Cerebrovascular Disease 2017

45. Case 1 DOACs: no data, cannot be recommended
However, there is reasonable non-randomized data suggesting LAAC can be performed safely in these patients, hence this should be the first choice

46. Reddy et al. JACC VOL . 69 , NO.3, 2017

47. Warfarin
DOACs
Watchman
Disabling stroke
ICH
All cause death
All major bleeding