Ponencia presentada por el Dr. Paul Guedeney en la Reunión EuroIMAT 2020, celebrada en Barcelona (20 y 21 de febrero de 2020).

1. Antithrombotic
treatment in TAVR
Paul Guedeney, MD
Paris-Sorbonne Université,
Institut de Cardiologie, Pitié-Salpêtrière, APHP
ACTION Study Group (www.action-coeur.org)
Paris, France

2. Disclosure of interest
• I have no potential conflict of interest

3. Periprocedural anticoagulation
in TAVR
« All quiet on the western front »

4. ACT-guided vs. Body weight-guided
UFH
Bernelli et al., JACC Cardiovasc Interv. 2014 Feb;7(2):140-151
Protective OR for ACT-guided UFH on major bleeding : 5,9 [2.8 to 12.6] ; p< 0.001) at 30 days.

5. Bernelli et al., JACC Cardiovasc Interv. 2014 Feb;7(2):140-151

6. Bivalirudin as alternative to UFH?
The BRAVO 3 trial
Bernelli et al., JACC Cardiovasc Interv. 2014 Feb;7(2):140-151

7. Periprocedural cerebral
protection

8. Van Belle et al., J Am Coll Cardiol. 2016;68(6):589-599.
Exemple of captured
proteoglycan-rich arterial
wall

9. CLEAN TAVI trial
Haussig et al, JAMA 2016, 316:592-601

10. HaussigS, Linke A et al, JAMA 2016, 316:592-601

11. Patient level analysis of protection
devices studies
Significant reduction of all all-cause mortality or stroke
2.1% vs 6.0% OR 0,34 (0.17-0.68)
Seeger et al., Eur Heart J. 2019;40(17):1334-1340.

12. Stroke, AF and bleedings
following TAVR

13. Pre-existing atrial fibrillation
CARDIOVASCULAR EVENTS IN STUDIES FROM 2017
Publication Year Study Type N STS-score Pre-existing AF
PARTNER 2A 2017 RCT 1011 5.8±2.1 31.0%
SURTAVI 2017 RCT 864 4.4±1.5 28.1%
PARTNER 3 2019 RCT 496 1.9±0.7 15.7%
Evolute Low Risk 2019 RCT 734 1.9±0.7 15.5%
STS/ACC TVT 2017 Registry 21575 6.8 [4.5,10.3] 41.2%
Swiss TAVI 2018 Registry 3493 5.8±4.4 N/A
WIN-TAVI 2018 Registry 1019a 8.3±7.4 20.0%
SOURCE 3 2017 Registry 1946 N/A 22.6%
FORWARD 2018 Registry 1060 5.5±4.5 34.5%
GARY 2019 Registry 6062 2.9±0.72 18.8%
FRANCE TAVI 2019 Registry 12804 10.1±9.9 33.3%
N= 50,045 patients. Average pre-TAVI AF = 26%

14. Stroke rate post-TAVR
Average stroke rate at 30 days and one year 3.14% and 5.14%
CARDIOVASCULAR EVENTS IN STUDIES FROM 2017
Publication Year Study Type N Stroke at 30d Stroke at 1 year
PARTNER 2A 2017 RCT 1011 6.4% 10.4%
SURTAVI 2017 RCT 864 4.5% 8.2%
PARTNER 3 2019 RCT 496 0.6% 2.2%
Evolute Low Risk 2019 RCT 734 4.0% 5.8%
STS/ACC TVT 2017 Registry 21575 2.5% 4.1%
Swiss TAVI 2018 Registry 3493 3.8% 4.9%
WIN-TAVI 2018 Registry 1019a 1.3% 2.2%
SOURCE 3 2017 Registry 1946 2.0% 4.3%
FORWARD 2018 Registry 1060 3.2% 4.4%
GARY 2019 Registry 6062 N/A N/A
FRANCE TAVI 2019 Registry 12804 N/A N/A

15. Post-TAVR stroke
Evolving risks and risk factors
Stortecky et al, circulation 2012 ; 126(25): 2921-4

16. Bleeding risk following TAVR
16,8
9,3
12,7
13,6
10,4
1,2
2,4
22,3
14,7
17,6
16,6
15,2
2,8 3,2
0
5
10
15
20
25
PARTNER-IB, 2010 PARTNER-IA, 2011 U.S. Corevalve-
Extreme risk, 2014
U.S. Corevalve-High
risk, 2014
PARTNER 2, 2016 PARTNER 3, 2019 Evolut Low Risk, 2019
Within 30 days Within 1 one year
Reported incidence of life-threatening or disabling bleeding
In major randomized controlled trials
%

17. Late bleeding and mortality after TAVI
Généreux et al. JACC 2014; 64: 2605-15

18. Antithrombotic Treatment for
the device

19. Subclinical leaflet thrombosis
Chakravarty et al., Lancet. 2017 389(10087):2383-2392

20. Subclinical leaflet thrombosis
De Baker et al.,N Engl J Med 2020; 382:130-139

21. Subclinical leaflet thrombosis
Chakravarty et al., Lancet. 2017 389(10087):2383-2392

22. Impact of antithrombotic treatment
Chakravarty et al., Lancet. 2017 389(10087):2383-2392

23. Waksman et al., J Am Coll Cardiol 2018;72:2095–105

24. Multiple mechanisms involved
Midha.,Circulation. 2017;136:1598–1609

25. Correlates of Bioprosthetic Valve Dysfunction
N=2555 m=20
P-value
Adj. OR 95% CI
upper
95% CI
lower
BMI 0.002 1.05 1.02 1.09
Prior TAVR 0.025 2.96 1.15 7.64
Moderate/severe renal
failure
0.034 1.46 1.03 2.08
Non-femoral access 0.049 0.53 0.28 1.02
Prosthesis ≤23 mm <0.001 3.43 2.41 4.89
OAC at discharge 0.005 0.54 0.35 0.82
Overtchouk et al., J Am Coll Cardiol. 2019 Jan 8;73(1):13-21.

26. Dangas et al., J Am Coll Cardiol 2016;20:68(24):2670-2689

27. Clinical impact of leaflet thrombosis
MACCE
Rashid et al., EuroIntervention 2018;13:e1748-e1755

28. ETIOLOGY OF THROMBOEMBOLIC
EVENTS AFTER TAVI
To obviate stent-mediated risk of platelet-related
thrombosis/embolization
=> Use of DAPT
To prevent thrombin-based thrombus formation during
the first 3 months after implantation
=> Use of OAC
A clearer mechanistic understanding of the pathobiology of
thromboembolic events during and after TAVI will provide a
translatable foundation for optimal therapies
Antiplatelet Hypothesis Antithrombin Hypothesis

29. How do we proceed in real life?

30. Pending issues
• Anticoagulation or antiplatelet after TAVI?
• If antiplatelet, DAPT or SAPT?
• If anticoagulation, can NOAC be used after TAVI?
Nijenhuis et al., Heart. 2019;105(10):742-748.

31. DAPT vs. SAPT?
The ARTE trial
Rodés-Cabau et al., JACC Cardiovasc Interv. 2017 Jul 10;10(13):1357-1365.

32. Maes et al., Am J Cardiol. 2018;122(2):310-315.
DAPT vs. SAPT?
Individual patient level analysis of 3 RCTs

33. Long-term Anticoagulation in TAVR
Overtchouk et al., J Am Coll Cardiol. 2019 Jan 8;73(1):13-21.
Adjusted HR 1.18 (95%CI 1.04-1.35)

34. Added value of antiplatelet therapy to
OAC post-TAVR?
Albdul-Jawad Altisent et al., JACC Cardiovasc Interv. 2016;9(16):1706-17

35. NOAC in TAVR
The higher ischemic event rate observed with NOACs needs to be evaluated in large randomized trials
Jochheim et al., JACC Cardiovasc Interv. 2019;12(16):1566-1576.

36. Antithrombotic treatment in
PARTNER-2
Chakravarty et al., J Am Coll Cardiol. 2019;74(9):1190-1200
(n=3889 patients) (n=943 patients)

37. Chakravarty et al., J Am Coll Cardiol. 2019;74(9):1190-1200

38. Ongoing Trials

39. Guedeney et al., Circ Cardiovasc Interv. 2019 Jan;12(1):e007411.

40. GALILEO (Global multicenter, open-label, randomized, event-driven, active-controlled
study comparing a rivAroxaban-based antithrombotic strategy to an antipLatelet-based strategy
after transcatheter aortIc vaLve rEplacement (TAVR) to Optimize clinical outcomes will compare
rivaroxaban-based)
• Open label, international,
multicenter, event-driven,
randomized, controlled trial
comparing a rivaroxaban-based
antithrombotic strategy vs. an
antiplatelet-based strategy post-
successful TAVR
• Primary efficacy endpoint: death,
stroke, MI, systemic
thromboembolism, symptomatic valve
thrombosis, or deep venous
thrombosis or pulmonary embolism
• Primary safety endpoint: VARC-2
major, disabling or life-threatening
bleeding
Dangas, N Engl J Med. 2020 Jan 9;382(2):120-129
Follow-up period:
30 days
DAPT:
Clopidogrel 75 mg od
+ ASA 75–100 mg
1–7 days
post-TAVR and before
hospital discharge
R 1:1
End of Rx90 days:
Drop 1 antiplatelet
Rivaroxaban 10 mg od
+ ASA 75–100 mg
Rivaroxaban 10 mg od
ASA 75–100 mg
Population:
Patients with
successful TAVR*
DSMB rec. Aug 2018
Ended f/u in Sept 2018
(total 1,644 pts)
Post-treatment
period

41. GALILEO trial
Dangas, N Engl J Med. 2020;382(2):120-129

42. Study Design
Study population:
Patients with
successful TAVR
1-7 days
R
Rivaroxaban
group
Antiplatelet
group
4DCT-scan at 3 months
1:1
De Backer et al., N Engl J Med. 2020;382(2):130-139.

43. 4DCT outcomes
Primary endpoint
De Backer et al., N Engl J Med. 2020;382(2):130-139.

44. POPULAR TAVI (NCT02247128)
Nihenjuis et al., Am Heart J. 2016 Mar;173:77-85

45. ATLANTIS (Anti-Thrombotic Strategy to Lower All cardiovascular and
Neurologic Ischemic and Hemorrhagic Events after Trans-Aortic Valve Implantation
for Aortic Stenosis)
Collet et al., Am Heart J. 2018 Jun;200:44-50.

46. ENVISAGE-TAVI AF Trial
RANDOMIZE 1:1
1-7 Days after the procedure
Background Tx: Single Antiplatelet Therapy as per treating
MD discretion (Stratification Variable)
Minimum duration of randomized therapy 12 months
EDOXABAN 60mg po daily
(Adjustment to
30mg for low eGFR )
Warfarin (target INR 2-3)
CLINICAL FOLLOW-UP: 1, 6, 12 Months
Secondary Endpoints
All-cause Death, MI, Stroke or TIA, VARC-2
Life-threatening (LT) bleeding and Major
bleeding
Primary Safety Endpoint: Major
Bleeding
Primary Endpoint - NACE
[Composite of Death, MI, Stroke, TIA, systemic
thromboembolism or VARC-2 Life-threatening (LT) or
Major bleeding]
Ancillary Studies
• Cost-Effectiveness
• QoL substudy
Successful TAVR n=1400
Patients With an Indication to Chronic Oral Anticoagulation
Van Mieghem et al., Am Heart J. 2018 Nov;205:63-69.

47. Stroke
– Not ↓ with DAPT vs. SAPT
– Not ↓ with ASA or clopidogrel added to OAC
Subclinical prosthesis thrombosis (HALT
& RELM≥3)
– Not  with DAPT vs. SAPT
–  With OAC vs. APT
Bleedings
– ↑ with DAPT vs. SAPT
– ↑ with ASA or clopidogrel added to OAC
Myocardial infarction
– ↓ With DAPT vs. SAPT
– Not ↓ with OAC vs. APT
Bleedings
~10%
Stroke
~5%
Subclinical prosthesis
thrombosis
HALT ~40%
RLM ~6%
Myocardial infarction
~2%

48. O A COral anticoagulation
(VKA and consider NOAC)
ASA 75–100 mg daily Clopidogrel 75 mg daily
lifelong
3-6 months@
No indication for
OAC
DAPTDual therapy
O A or C
Indication for OAC
OAC
Monothe
rapy
O
OAC
Monotherapy
O
Recent ACS or coronary stenting
Yes
OAC SAPT*
Unfractionated heparin (ACT≥250-300 seconds)#
Post-TAVI
SAPT
A or C
SAPT
A or C
Yes
A C
* ASA or P2Y12 inhibitor, # Bivalirudin if HIT, @ duration according to bleeding risk
Pre-TAVI
TAVI
No No

49. Conclusions
• The bioprosthetic valve adds a prothrombotic environment
• AF and NOAF are strong determinants of CVE
• Antithrombotic regimens are (so far) based of expert consensus
and influenced by patient comorbidities
• It is challenging especially within the low risk population

50. Thank you