Upload
others
View
1
Download
0
Embed Size (px)
Citation preview
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!