Braveheart. NOAC in AF patients after coronary stenting

NOAC in AF patients after coronary stenting
Dr. Raúl Moreno
Hospital La Paz - Madrid, Spain
BRAVEHEART
Fotoretiradadelapelícula“Braveheart”utilizadaparafineseducativos
segúnelart32delaLPI.

• 5-7% patients undergoing PCI have indication for oral
anticoagulation due to AF.
• These patients are at high risk of both thrombotic and bleeding
events.
• Treatment: wide variation in clinical practice.
• Two separate aspects of anti-thrombotic treatment:
– Double versus triple therapy.
– NOAC vs vKA.
HOW IMPORTANT IS THIS PROBLEM
NOAC in AF patients after coronary stenting Dr. Raúl Moreno

IMPACT OF POST-DISCHARGE BLEEDING AFTER PCI
(ADAPT-DES STUDY)
Impact of post-discharge bleeding vs MI on mortality
 8583 patients treated with ≥ 1 DES prospectively followed-up in 10-15 hospitals.
 Platelet reactivity evaluated using VerifyNow showed increased risk of events with high PRU.

BRAVEHEART
NOAC in AF patients after coronary stenting
Dr. Raúl Moreno
Hospital La Paz - Madrid, Spain
Fotoretiradadelapelícula“Braveheart”utilizadaparafineseducativos
segúnelart32delaLPI.

ALL OPTIONS CAN BE GOOD, BAD, AND UGLY AT THE SAME
TIME
DAPT Anticoagulation
Prevention of stent
thrombosis &
reinfarction
Prevention of stroke

DUAL VERSUS TRIPLE THERAPY IN POST-PCI PATIENTS
WITH AF
 11,480 patients with AF and
MI or post-PCI (2000-2009)
in Denmark.
 Bleeding events accordingly
to the type of anti-thrombotic
therapy.
Triple therapy: the problem of bleeding

• 583 patients with indications for OAC undergoing PCI (98% stent, 2/3 DES).
• Randomization to doublé (clopi+VKA) vs triple (ASA+Clopi+VKA) therapy.
DOUBLE VERSUS TRIPLE ANTI-PLATELET THERAPY: WOEST
TRIAL

DOAC VERSUS VKA: THE PUZZLE HAS BEEN COMPLETED
Rivaroxaban
(PIONEER)
Apixaban
(AUGUSTUS)
Dabigatran
(RE-DUAL)

Significantly lower rates of ISTH major bleeding or CRNMBE with
dabigatran dual therapyProbabilityofevent(%)
0
0 90 180 270 360 450 540 630 720
Time to first event (days)
40
35
30
25
20
15
10
5
Warfarin
triple therapy
Dabigatran 110 mg
dual therapy
HR: 0.52 (95% CI: 0.42–0.63)
Non-inferiority P<0.001
P<0.001
0 90 180 270 360 450 540 630 720
Time to first event (days)
40
35
30
25
20
15
10
5
0
Dabigatran 150 mg
dual therapy
Warfarin
triple therapy
HR: 0.72 (95% CI: 0.58–0.88)
Non-inferiority P<0.001
P=0.002
2,725 NVAF patients post-CS: warfarin+ASA vs Dabigatran 110 mg BID vs 150 mg BID (all P2Y12 inhibitor).
Primary end point: major or clinically relevant nonmajor bleeding event.
RE-DUAL PCI trial

No significant differences in efficacy end-points among 3 groups
Composite efficacy end point:
Death, thromboembolic events (MI, stroke, or systemic embolism), or unplanned revascularization.
Cannon et al. N Engl J Med. 2017 Oct 19;377(16):1513-1524.
RE-DUAL PCI trial

PIONEER-AF trial
2,124 NVAF patients undergoing CS
Group 1: Riva 15 mg + P2Y12
Group 2: Riva 2.5 mg b.i.d. + DAPT followed by Riva 15 mg + P2Y12
Group 3: VKA + DAPT

My concern with low-dose NOAC: stent thrombosis (trials
unpowered)
RE-DUAL PCI PIONEER AF
≈ 11% of patients
included had
STEMI
≈ 12% of patients
included had
STEMI

AUGUSTUS trial
ACS PCI
37.3%23.9% 38.8%
76.1%61.2%
• 4,614 patients with AF after ACS and/or PCI.
• 6-month follow-up (!)
2x2 randomization
• Apixaban (standard dose) vs VKA.
• ASA 81 mg/d vs placebo
(in association with any P2Y12 inhibitor ≥ 6
mo).
Primary end-point: major or clinically relevant bleeding through 6 months.

10.5
%
14.7%
9.0%
16.1%
Major or CRNMB: Apixaban vs VKA. Major or CRNMB: ASA vs placebo.
AUGUSTUS trial

ENTRUST-AF
• 1,506 patients with AF after PCI-stent.
• Randomization (1:1 design) to: Edoxaban + P2Y12 inhibitor or vKA + ASA 100 mg/d + P2Y12 inhibitor.
• Primary end-point: major or clinically relevant non-major bleeding at 12 months.
17.0% (20.7% annualized)
20.0% (25.6% annualised)

Figure S6. Kaplan-Meier curve for the main efficacy endpoint, ITT analysis
0·10
0·09
0·08
0·07
0·06
0·05
0·04
0·03
0·02
0·01
0·00
0 30 60 90 120 150 180 210 240 270 300 330 360
Days from randomisation
EDOXABAN
Number at risk:
751 719 705 695 685 679 670 664 657 652 643 639 575
VKA 755 718 700 690 678 667 661 657 653 646 640 635 575
Edoxaban VKA
Number of events:
Edoxaban: 49/751
VKA: 46/755
HR (95% CI): 1·06 (0·71; 1·69)
Cumulativeincidenceinoutcomes
Main efficacy outcome
(CV death, stroke, systemic embolic events, MI, and definite stent thrombosis)
ENTRUST-AF

Timing and bleedings
Hypothesis: investigators were concerned
about bleeding risk with VKA and
undertreated these patients
ENTRUST-AF

4,510 out of 21,105 patients (21.4%) had previous CAD.
4,5
3,2
3,6
2,5
Prior CAD No prior CAD
VKA Edoxaban 60
Major bleeding (annualized rate).
Putting into context the ENTRUST: CAD patients in the ENGAGE
ARR: 0.9%
RRR: 20%
ARR: 0.7%
RRR: 22%
1,2 1,2
0,7 0,6
Prior CAD No prior CAD
VKA Edoxaban 60
Fatal or life-threatening bleeding
ARR: 0.5%
RRR: 42%
ARR: 0.6%
RRR: 50%

4,510 out of 21,105 patients (21.4%) had previous CAD.
5,4
3,2
4,4
2,6
Prior revasc No prior revasc
VKA Edoxaban 60
Major bleeding (annualized rate).
ARR: 1,0%
RRR: 19%
ARR: 0.6%
RRR: 19%
1,4
1,1
0,9
0,6
Prior revasc No prior revasc
VKA Edoxaban 60
Fatal or life-threatening bleeding
ARR: 0.5%
RRR: 36%
ARR: 0.5%
RRR: 45%
Putting into context the ENTRUST: CAD patients in the ENGAGE

Putting into context the ENTRUST: concomitant use of SAPT
in the ENGAGE

SAGE Open Medicine
SAGEOpen Medicine
3: 2050312115613350
© The Author(s) 2015
Reprintsand permissions:
sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/2050312115613350
smo.sagepub.com
Systematic review and network meta-analysis
of the relative efficacy and safety of edoxaban
versusother nonvitamin K antagonist
oral anticoagulantsamong patientswith
nonvalvular atrial fibrillation and
CHADS2 score⩾ 2
Maria M Fernandez1, Jianmin W ang1, Xin Ye2,
W inghan Jacqueline Kwong2, Bintu Sherif1, Susan Hogue1
and Beth Sherrill1
Abstract
Background: The nonvitamin K antagonist oral anticoagulants pivotal clinical trialsfor stroke prevention in atrial fibrillation
have important differences in trial designs and baseline patient characteristics.
Objective: We sought to evaluate the relative efficacy and safety of edoxaban versus other nonvitamin K antagonist oral
anticoagulants in the management of stroke prevention in atrial fibrillation by adjusting for differences in baseline stroke risk
and the length of follow-up amongthe four phase 3 randomized controlled trials.
Methods: We conducted a systematic literature review of randomized controlled trials evaluating the nonvitamin K
antagonist oral anticoagulants for stroke prevention in atrial fibrillation and performed a network meta-analysis using data
from ENGAGE AF-TIMI 48, RE-LY, ROCKET-AF, and ARISTOTLE, with warfarin as a common comparator. To adjust for
between-trial differences in CHADS2 score and length of follow-up, annualized event rates among patients with CHADS2
score⩾ 2 were analyzed usingamixed Poisson’s regression model.
Results: Once-daily high-dose edoxaban was associated with significant lower major bleeding episodes compared with once-
daily rivaroxaban (risk ratio, 0.76; 95% confidence interval, 0.66–0.89), twice-daily dabigatran 150mg (risk ratio, 0.78; 95%
confidence interval, 0.61–0.84), and twice-daily dabigatran 110mg (risk ratio, 0.83; 95% confidence interval, 0.71–0.98) and
similar bleedingrisk compared with twice-daily apixaban (risk ratio, 1.08; 95%confidence interval, 0.91–1.28). Risk of stroke and
systemic embolism wassimilar for the high-dose edoxaban and other nonvitamin K antagonist oral anticoagulant regimens. The
low-dose edoxaban regimen was associated with asignificant lower risk of major bleedingthan other nonvitamin K antagonist
oral anticoagulantsand asignificant higher risk of stroke and systemic embolism compared with apixaban and dabigatran 150mg.
613350SMO0010.1177/20503121 15613350 SAGE Open Medicine Fernandez et al.
h-article 2015
Original Article
• Four phase 3 pivotal trials for stroke prevention in
AF (RE- LY, ROCKET-AF, ARISTOTLE, and ENGAGE
AF-TIMI 48).
• Network meta-analysis including only data from
patients with CHADS2 score⩾2 in RE-LY and
ARISTOTLE.
Major bleeding Stroke and systemic embolism
Putting into context the ENTRUST

CONCLUSIONS
• With the ENTRUST trial, the puzzle of NOAC in patients with AF and PCI-
stent is completed.
• In ENTRUST, edoxaban was not inferior to VKA in terms of bleeding
complications, with similar rate of cardiac events.
• The risk reduction in bleeding, although not statistically significant, was
consistent with the benefit observed in other edoxaban trials.
• Edoxaban is now an alternative to other NOAC in patients treated with
PCI-stent and AF.

Braveheart. NOAC in AF patients after coronary stenting

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