Anti-thrombotics for ACS in AF Patients

Atul Verma MD FRCPC FHRSDirector, Heart Rhythm Program

Southlake Regional Health CentreAssociate Professor, University of TorontoScientist, Li Ka Shing Knowledge Institute

Disclosures• Research Grants – Bayer, Biotronik, Bristol Meyers Squibb, Cardiostat, Medtronic

• Advisory Board – Acutus, Ablacon, Adagio Medical, Bayer, Biosense Webster, Kardium, Medtronic, Medlumics, Thermedical, Volta Medical

• Clinical trials - Acutus, Ablacon, Biosense Webster, Medtronic, Thermedical

• No ownership, stock options, patents, or other financial interest

Introduction

• At-risk patients with AF require full oral anticoagulation (preferably with a non-vitamin K anticoagulant, NOAC) for stroke prevention

• Patients post-PCI require anti-platelet therapy for prevention of recurrent ACS and/or stent thrombosis

• Dual or triple anti-thrombotic therapy is associated with increased bleeding which can contribute to increased mortality

Providing the Best Protection in Patients with AF and ACS/PCI

Adapted from Capodanno D, et al. JACC Cardiovasc Interv 2017; 10:1086-8.5

Anti-coagulant therapyThrombus in the left atrium

Low shear stress

Antiplatelet therapy (additive benefit oral anticoagulant?) Thrombus,

platelet mediated in the coronary artery

High shear stress

PCI AF

AF

PCI

VKADabigatranRivaroxabanApixabanEdoxaban

AspirinClopidogrelPrasugrelTicagrelor

TIA/StrokeOAC > DAPT

Stent ThrombosisDAPT > OAC

TripleTherapy

Balance of Risk and Benefit

2018 Focused Update CCS AF Guidelines, Can J Cardiol

2018 CCS AF Recommendations

High risk features:DMSmokerRenal dysfunctionPrior ACSPrior stent thrombosisMultivessel diseaseMultiple stentsComplex bifurcation lesionStent length >60 mmCTOBioabsorbable stent

Preferred NOAC doses:Rivaroxaban 15 mg ODDabigatran 110-150 mg BIDApixaban 5 mg ODEdoxaban 60 mg OD

Canadian Cardiovascular Society Guidelines for Patients with Atrial Fibrillation, Coronary or Vascular Disease and an Indication for OAC*

• “For patients with AF aged ≥65 years or with a CHADS2 score ≥1, we suggest dual pathway therapy (an OAC with clopidogrel 75 mg/d) for at least 1 month after BMS implantation and at least 3 months after DES implantation for elective PCI”

• For patients with AF aged ≥65 years or with a CHADS2 score ≥1, we recommend an initial regimen of triple therapy (ASA 81 mg/d with clopidogrel 75 mg/d with an OAC) up to 6 months after PCI associated with ACS or high-risk PCI

• After ASA discontinuation, which may occur as early as the day after PCI, we suggest that dual pathway therapy (an OAC with clopidogrel 75 mg/d) be continued for up to 12 months after PCI”

Andrade JG, et al. Can J Cardiol 2018; 34:1371-92.8

Drug Dabigatran Rivaroxaban Apixaban Edoxaban

Trial RE-DUAL1 PIONEER2 AUGUSTUS3 ENTRUST-PCI4

Enrollment 2725 2124 4614 1506

Key Inclusion AF + PCI (elective or not) AF + PCI (elective or not) + stent AF + ACS and/or PCI AF + PCI + stent

Key exclusionRecent use of fibrinolytics, stroke or major bleeding within 1 month,

CrCl < 30 ml/min

History of stroke or TIA, GI bleed within 12 months,

CrCl < 30 ml/min

History of ICH, ongoing bleeding,

coagulopathy, CrCl < 30 ml/min

Stroke within 2 weeks, known bleeding diathesis, CrCl < 15

ml/min

Studied regimens110mg + P2Y12150mg + P2Y12

War (INR 2-3) + DAPT

15mg + P2Y122.5mg + DAPT

War (INR 2-3) + DAPT

5mg + P2Y12War (INR 2-3) + P2Y12

5mg + DAPTWar (INR 2-3) + DAPT

60mg + P2Y12VKA + DAPT

ASA duration in DAPT arm (protocol)

1 month in bare-metal stent, 3 months in drug-eluting stent 1, 6 or 12 months 6 months

Risk-based: 30 days to 12 months

Time from event (or PCI) to randomisation

Between 6h and 120h(actual time not available)

Within 72h of sheath removal (actual time not

available)

Within 14 days of ACS or PCI (mean 6.6 days;

median 6 days)

Between 4h and 5 days (median 45.1h)

TTR in VKA arm Mean 64% Mean 65% Mean 56% (median 59%) Mean 60% (median 63.1%)

Randomized Trials of NOACs Following PCI: Selected Characteristics

9 Adapted from: 1. Cannon CP, et al. N Engl J Med 2017; 377(16):1513-24; 2. Gibson CM, et al. N Engl J Med 2016; 375(25):2423-34;3. Lopes RD, et al. N Engl J Med 2019; 380:1509-24; 4. Vranckx P, et al. Lancet 2019; 394(10206):1335-43.

Patients With AF Undergoing Coronary Stent Placement: PIONEER AF-PCI Study

• Primary endpoint: TIMI major + minor + bleeding requiring medical attention • Secondary endpoint: CV death, MI, and stroke

Patients with paroxysmal, persistent or permanent NVAF undergoing PCI (with stent placement)

RANDOMIZE

1,6, or 12 months

Rivaroxaban 15 mg qd*Clopidogrel 75 mg qd†

Rivaroxaban 15mg QDAspirin 75-100 mg qd

Rivaroxaban 2.5 mg bidClopidogrel 75 mg qd†Aspirin 75-100 mg qd‡

VKA∆(target INR 2.0-3.0)

Aspirin 75-100 mg qdVKA∆ (target INR 2.0-3.0)Clopidogrel 75 mg qd†Aspirin 75-100 mg qd

≤72hours

AfterSheath removal

1,6, or 12 months

End oftreatment12 months

WOEST Like

ATLAS Like

TripleTherapy

Pre randomization MD Choice

Pre randomization MD Choice

*Rivaroxaban dosed at 10 mg once daily in patients with CrCl of 30 to

PIONEER AF-PCI: Both Rivaroxaban Strategies Were Associated With Significantly Improved Safety vs. VKA

Gibson CM, et al. N Engl J Med 2016; 375(25):2423-34.

0

5

10

15

20

25

30

TIM

I maj

or, T

IMI m

inor

or b

leed

ing

requ

iring

med

ical

atte

ntio

n (%

)Rivaroxaban 15 mg OD plus single antiplatelet vs VKA plus DAPT: HR=0.59; (95% CI 0.47–0.76); p

Efficacy was Comparable Between All Three Treatment Strategies*

*Trial not powered to definitively demonstrate either superiority or non-inferiority for efficacy endpoints (if so, a total of 40,794 patients across groups will be needed, with at least 13,598 patients in each arms)

Gibson CM et al, New Engl J Med 2016; doi: 10.1056/NEJMoa1611594

CV

deat

h, M

I or s

trok

e (%

)

Time (days)

8

6

4

2

00 30 60 90 180 270 360

Group 2 (Rivaroxaban 2.5 mg BID plus DAPT)Group 1 (Rivaroxaban 15 mg OD plus single antiplatelet)

Group 3 (VKA plus DAPT)

6.0%5.6%

6.5%

Rivaroxaban 15 mg OD plus single antiplatelet vs VKA plus DAPT: HR=1.08; (95% CI 0.69–1.68); p=0.75Rivaroxaban 2.5 mg BID plus DAPT vs VKA plus DAPT: HR=0.93 (95% CI 0.59–1.48); p=0.76

28.4%

20.3%20.3%

10.5%

5.4%6.5%

CV

Bleeding

30

20

10

00

Prop

ortio

n of

pat

ient

s w

ho w

ere

reho

spita

lized

(%)

30 60 90 180 270 360Time (days)

Adverse events leading to hospitalization were classified by consensus panel blinded to treatment group as potentially related to either bleeding, CV or other causes; Re-hospitalizations do not include the index event and include the first re-hospitalization after the index event.Gibson CM et al, Circulation 2016; doi:10.1161/CIRCULATIONAHA.116.025783

Re-hospitalization Due to CV Events and Bleeding Were Both Reduced with the Rivaroxaban Strategies

Group 2 (Rivaroxaban 2.5 mg BID plus DAPT)

Group 1 (Rivaroxaban 15 mg OD plus single antiplatelet)

Group 3 (VKA plus DAPT)

Group 1 vs Group 3: HR=0.68; (95% CI 0.54–0.85); p

14

15

16

17

18

AUGUSTUS Study with Apixaban: Design

19

*Major: bleeding resulting in death, occurring in a critical organ (intracranial, intraspinal, intraocular, retroperitoneal, intraarticular, intramuscular with compartment syndrome, or pericardial), or associated with either a decrease in the hemoglobin level of at least 2 g/dL or a transfusion of at least 2 units of packed red cells; Clinically relevant non-major: bleeding resulting in hospitalization, medical or surgical intervention for bleeding, an unscheduled clinic visit, or a change in physician-directed antithrombotic therapy

Lopes RD, et al. N Engl J Med 2019; 380:1509-24.

• P2Y12 inhibitor for all patients x 6 months• Aspirin for all on the day of ACS or PCI• Aspirin vs. placebo after randomization

Inclusion• NVAF or flutter

(active or history) with planned or existing OAC use

• Planned OAC use ≥1-6 months

• ACS and/or PCI withstent ≤14 days

Apixaban2.5 mg or 5 mg

twice daily

Warfarin

Aspirin

Placebo

Aspirin

Placebo

Primary outcome:major/clinically relevant

bleeding* (through 6 months)

Secondary objective:death, MI, stroke, stent

thrombosis

R

N=4600

20

AUGUSTUS Study (Apixaban vs. Warfarin):Major / Clinically Relevant Bleeding (Primary Endpoint)

Lopes RD, et al. N Engl J Med 2019; 380:1509-24.21

Vit K antagonist 2259 1984 1861 1795 1736 1686 1079

Apixaban 2290 2110 2019 1957 11902 1858 1037

No. At Risk

0102030405060708090

100

0 30 60 90 120 150 180

Cum

ulat

ive

Inci

denc

e of

eve

nt(%

)

Days since start of intervention

0

5

10

15

20

0 30 60 90 120 150 180

Event rate per 100 patient-yr:

Vitamin K antagonist, 35.8

Apixaban, 24.7

Hazard ratio for apixaban vs. Vitamin Kantagonist, 0.69 (95% CI, 0.58-0.81)P

AUGUSTUS Study (Apixaban vs. Warfarin): Major / Clinically Relevant Bleeding (Including Aspirin Randomization)

22 Lopes RD, et al. N Engl J Med 2019; 380:1509-24.

Apixaban / Aspirin 1145 1036 975 937 903 880 485Apixaban / Placebo 1143 1075 1044 1007 975 947 536

VKA / Aspirin 1123 962 881 838 800 776 467VKA / Placebo 1126 1007 947 917 833 851 528

No. At Risk

0

5

10

15

20

0 30 60 90 120 150 180

Cum

ulat

ive

Inci

denc

e of

eve

nt(%

)

Days since start of intervention

Apixaban + Placebovs. VKA + Aspirin:11.4% absolute riskreduction (NNT=9)

Apixaban + Aspirin (13.8%)

Apixaban + Placebo (7.3%)

VKA + Aspirin (18.7%)

VKA + Placebo (10.9%)

23

24

ENTRUST-AF PCI Study with Edoxaban: Design

See lecture notes for description of *, †, ‡ and §Adapted from Vranckx P, et al. Lancet 2019; 394(10206):1335-43.

4 hours –5 daysafter

sheath removal

Inclusion Criteria:• OAC indication for

AF for at least 12 months

• Successful PCI with stent placement (goal of at least 25% ACS)

P2Y12 inhibitor†(without aspirin)

P2Y12 inhibitor aspirin 1 - 12 months§

PROBE design: Prospective, Randomized, Open label, Blinded endpoint Evaluation in 1500 AF patients with ACS or stable CAD

Edoxaban 60 mg/day*

Vitamin K Antagonist‡

Primary outcome: ISTH major or clinically relevant non-

major bleeding, baseline to 12 months

RANDOMIZE

12 m.

25

ENTRUST-AF PCI: Major or Clinically Relevant Non-major Bleeding (Primary Endpoint)

ITT Analysis (N=1506), overall study period Adapted from Vranckx P, et al. Lancet 2019; 394(10206):1335-43.26

Edoxaban 751 688 665 646 629 618 609 600 590 584 575 565 506

VKA 755 678 648 625 603 588 578 568 561 552 543 538 485

No. At Risk

0.00

0.05

0.10

0.15

0.20

0.25

0 30 60 90 120 150 180 210 240 270 300 330 360 390

Cum

ulat

ive

Inci

denc

e in

out

com

es

Days from randomization

Number of events:Edoxaban: 128/751VKA: 152/755

HR (95% CI): 0.83 (0.65; 1.05)P-value (non-inferiority): 0.001P-Value (superiority): 0.1154

VKA

Edoxaban

ENTRUST-AF PCI: INR in VKA Regimen in First 5 Weeks

Adapted from Vranckx P, et al. Lancet 2019; 394(10206):1335-43.

Time from PCI toRandomisation: • shortest – 0.2 h• median – 45 h

27

Overall study period: median TTR = 63.1%

0%10%20%30%40%50%60%70%80%90%

100%

≤ Day 1 Day 2 to 7 Day 8 to14

Day 15 to21

Day 22 to28

Day 29 to35

mean INR < 2 mean INR 2-3

94%

69%

42% 37% 37% 39%

5%

23%

34% 40% 44%44%

8%24% 22% 19% 17%

1%

ENTRUST-AF PCI: Post Hoc Landmark Analysis of the Primary Endpoint (Major or Clinically Relevant Non-major Bleeding)

Vranckx P, et al. Lancet 2019; 394(10206):1335-43.28

Edoxaban 751 688 665 646 629 618 609 600 590 584 575 565 506

VKA 755 678 648 625 603 588 578 568 561 552 543 538 485

No. At Risk

0.00

0.05

0.10

0.15

0.20

0.25

0 30 60 90 120 150 180 210 240 270 300 330 360 390

Cum

ulat

ive

Inci

denc

e in

out

com

es

Days from randomization

Phase 1 (≤ day 14) HR (95% CI): 2.42 (1.27; 4.63)Phase 2 (> day 14) HR (95% CI): 0.68 (0.53; 0.88)Interaction P-value:

Meta-Analysis of Comparative NOAC AF PCI Trials:ISTH Major or CRNM Bleeding

Vranckx P, et al. Lancet 2019; 394(10206):1335-43 (supplementary materials).29

NOAC DAT VKA TAT Risk Ratio Risk Ratio

Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI

AUGUSTUS 84 1143 210 1123 23.7% 0.39 (0.31, 0.50)

ENTRUST AF-PCI 128 751 152 755 24.7% 0.85 (0.68, 1.05)

PIONEER AF-PCI 117 696 178 697 24.8% 0.66 (0.53, 0.81)

RE-DUAL PCI 305 1744 264 981 26.8% 0.65 (0.56, 0.75)

Total (95% CI) 4334 3556 100.0% 0.62 (0.47, 0.81)

Total events 634 804

Heterogeneity: Tau² = 0.07; Chi² = 22.84, df = 3 (P

Meta-Analysis of Comparative NOAC AF PCI Trials:Myocardial Infarction and Stent Thrombosis

Vranckx P, et al. Lancet 2019; 394(10206):1335-43 (supplementary materials).30

NOAC DAT VKA TAT Risk Ratio Risk RatioStudy or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CIAUGUSTUS 38 1153 34 1154 29.3% 1.12 (0.71, 1.76)ENTRUST AF-PCI 29 751 23 755 21.0% 1.27 (0.74, 2.17)PIONEER AF-PCI 19 694 21 695 16.2% 0.91 (0.49, 1.67)RE-DUAL PCI 70 1744 29 981 33.5% 1.36 (0.89, 2.08)Total (95% CI) 4342 3585 100.0% 1.18 (0.93, 1.53)Total events 156 107

Myocardial Infarction

Heterogeneity: Tau² = 0.00; Chi² = 1.25, df = 3 (P

Thank you!

Anti-thrombotics for ACS in AF Patients DisclosuresIntroductionSlide Number 4Providing the Best Protection in Patients with AF and ACS/PCIBalance of Risk and Benefit2018 CCS AF RecommendationsCanadian Cardiovascular Society Guidelines for Patients with Atrial Fibrillation, Coronary or Vascular Disease and an Indication for OAC*Randomized Trials of NOACs Following PCI: Selected CharacteristicsPatients With AF Undergoing Coronary Stent Placement: PIONEER AF-PCI StudyPIONEER AF-PCI: Both Rivaroxaban Strategies Were Associated With Significantly Improved Safety vs. VKAEfficacy was Comparable Between All Three Treatment Strategies*Slide Number 13Slide Number 14Slide Number 15Slide Number 16Slide Number 17Slide Number 18AUGUSTUS Study with Apixaban: DesignSlide Number 20AUGUSTUS Study (Apixaban vs. Warfarin):�Major / Clinically Relevant Bleeding (Primary Endpoint)AUGUSTUS Study (Apixaban vs. Warfarin): Major / Clinically Relevant Bleeding (Including Aspirin Randomization)Slide Number 23Slide Number 24ENTRUST-AF PCI Study with Edoxaban: DesignENTRUST-AF PCI: Major or Clinically Relevant Non-major Bleeding (Primary Endpoint)ENTRUST-AF PCI: INR in VKA Regimen in First 5 WeeksENTRUST-AF PCI: Post Hoc Landmark Analysis of the Primary Endpoint (Major or Clinically Relevant Non-major Bleeding)Meta-Analysis of Comparative NOAC AF PCI Trials:�ISTH Major or CRNM BleedingMeta-Analysis of Comparative NOAC AF PCI Trials:�Myocardial Infarction and Stent ThrombosisThank you!