Duplice o triplice terapia antitrombotica · Roberta Rossini, MD, PhD Dipartimento emergenza e aree...
Transcript of Duplice o triplice terapia antitrombotica · Roberta Rossini, MD, PhD Dipartimento emergenza e aree...
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Duplice o triplice terapia antitrombotica
Roberta Rossini, MD, PhDDipartimento emergenza e aree critiche
Ospedale S. Croce e CarleCuneo
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Conflicts of interest
Payment as an individual for consulting fee or honorarium
from:
• Astra Zeneca
• Bayer
• Boehringer
• Chiesi
• Daiichi Sankyo
• Novartis
• Pfizer
Institutional payments for unrestricted grants from:
• Chiesi
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• There is no (strong) evidence
• ST is still the worst complication
(with the exception of ICH)
• It is not a matter of sum, it’s a matter of addends
Triple antithrombotic therapy is the right choice
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ROCKET AF PIONEER AF
N of enrolled patients 14,264 2,124
Prior stroke/TIA 55% 0
Inclusion criterion AF within 30 days beforerandomization
AF that occurred within 1 yearbefore screening
Primary end-point Stroke or systemic embolism Clinically significant bleeding
Non-major clinically relevantbleeding
Bleeding requiring medicalintervention, unscheduledcontact temporaryinterruption of study drug,pain, or impairment of dailyactivities.
A bleeding event requiringmedical attention is defined asany bleeding event thatrequires medical treatment, surgical treatment, or laboratory evaluation
Mean CHADS-VASC 0-1 0 10%
Comparison between ROCKET AF and PIONEER-AF
The PIONEER:
• Open-label design
• “Underpowered” to assess ischemic events
• Selection bias? The trial enrolled 5 pts per Center in 3 yrs
• Up to 30% of pts permanently discontinued the treatment before the scheduled termination date
• 1 out of 2 pts in the triple Tx groups were assigned to DAPT for 12 mo
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• Would you ever treat an AF pt with rivaroxaban 2,5 bid?
• Would you ever prolong triple TX up to 12 months?
• We do not have rivaroxaban 10 mg (for pts with clearance creatinine <50 treated with double TX according to the PIONEER trial)
Triple antithrombotic therapy is the right choice
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• The primary endpoint was time to first ISTH major or clinically relevant non-major
bleeding
• Formally tested and powered endpoints included:
– Non-inferiority of 110 mg and 150 mg dual therapy groups on time to first ISTH
major or clinically relevant non-major bleeding event.
– Non-inferiority of both dual therapy groups combined on time to first event of death,
thromboembolic event (MI, stroke, systemic embolism) or unplanned
revascularization
– Superiority testing of the bleeding endpoints
• 100% of outcome events were independently adjudicated by blinded external committee
Study objective and design
RE-DUAL PCI tests the safety and efficacy of two regimens of dual therapy with
dabigatran without aspirin vs triple therapy with warfarin
N=2725
Cannon CP et al. N Engl J Med. 2017 Oct 19;377(16):1513-1524
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• Open-label design
• It was “Underpowered” to assess ischemic events in eachdabigatran arm
• No data on procedural features
• Selection bias? The trial enrolled 2725 pts in 414 Centers in 2 yrs, <6 pts per Center
• The protocol was amended and the comparison of thromboembolic-event rates in the two dual-therapy groupscombined versus the triple therapy group was changed to a secondary end point.
REDUAL-PCI Main limitations
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Additional individual thromboembolic endpoints
Dabigatran 110
dual therapy
(n=981) n (%)
Warfarin triple
therapy
(n=981)
n (%)
D110 DT vs warfarin TT
HR (95% CI)
P value
Dabigatran 150
mg dual
therapy
(n=763)
n (%)
Warfarin triple
therapy
(n=764)
n (%)
D150 DT vs warfarin TT
HR (95% CI) P value
All-cause death 55 (5.6) 48 (4.9) 1.12 (0.76–1.65) 0.56 30 (3.9) 35 (4.6) 0.83 (0.51–1.34) 0.44
Stroke 17 (1.7) 13 (1.3) 1.30 (0.63–2.67) 0.48 9 (1.2) 8 (1.0) 1.09 (0.42–2.83) 0.85
Unplanned
revascularization76 (7.7) 69 (7.0) 1.09 (0.79–1.51) 0.61 51 (6.7) 52 (6.8) 0.96 (0.65–1.41) 0.83
MI 44 (4.5) 29 (3.0) 1.51 (0.94–2.41) 0.09 26 (3.4) 22 (2.9) 1.16 (0.66–2.04) 0.61
Stent thrombosis 15 (1.5) 8 (0.8) 1.86 (0.79–4.40) 0.15 7 (0.9) 7 (0.9) 0.99 (0.35–2.81) 0.98
Cannon CP et al. N Engl J Med. 2017 Oct 19;377(16):1513-1524
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• Which dose of dabigatran would you use in dual Tx in an 81 yr-old pt?
• Would safety data be different if triple Tx were maintained for only 1 month in the REDUAL PCI?
Triple antithrombotic therapy is the right choice
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Outcome primario di sanguinamento (ITT analysis)
ITT population (N = 1506); overall study period.
Vranckx, P, et al. Lancet. 2019.
ITT population (N = 1506); overall study period.
Vranckx, P, et al. Lancet. 2019.
Edoxaban regimen
VKAregimen
Intent-to-treat analysisNumber of patients 751 755Number of patients with event (%) 128 (17) 152 (20)Annualized event rate (% per year)
20.7 25.6
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N Engl J Med 1998;339:1665-71
Triple antithrombotic therapy is the right choice
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• There is no (strong) evidence
• ST is still the worst complication
(with the exception of ICH)
• It is not a matter of sum, it’s a matter of addends
Triple antithrombotic therapy is the right choice
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Thrombosis is a Rare but Life-Threatening Complication
Stent Thrombosis
N= 126
Cardiac Death
Myocardial Infarction
16
3539
P. Urban, G. Guagliumi Circulation 2006, February 21
13.437 patients with FU up and/or MACE to 360 days
Mortality: 40.4%
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• There is no (strong) evidence
• ST is still the worst complication
(with the exception of ICH)
• It is not a matter of sum, it’s a matter of addends
Triple antithrombotic therapy is the right choice
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Warfarin (INR 2 to 3)Apixaban (5 mg BID*)
N = 4600Approximately 500 sites in 34 countries
Key Inclusion Criteria
➢ Aged ≥ 18 years.
➢ AF (prior, persistent/permanent, paroxysmal) or flutter
with planned or existing use of OAC.
➢ ACS and/or PCI within the prior 14 days.
➢ Planned use of P2Y12 inhibitor for at least 6 months.
Key Exclusion Criteria
➢ Other conditions that require anticoagulation eg, mechanical
heart valve, moderate/severe mitral stenosis, DVT, or PE.
➢ Serum creatinine > 2.5 [221 µmol/L] or CrCl < 30 mL/min.
➢ History of intracranial hemorrhage.
➢ Contraindications to VKA, apixaban, intended P2Y12 or ASA.
➢ Recent/planned CABG surgery for index ACS event.
➢ Patients with known ongoing bleeding.
➢ Patients with known coagulopathies.
ASA Placebo
P2Y12 inhibitor for all patients x 6 monthsAspirin for all on the day of ACS and/or PCI until randomization
Aspirin versus placebo after randomization
ACS, acute coronary syndrome; AF, atrial fibrillation; ASA, aspirin; BID, twice daily; CABG, coronary artery bypass graft; CrCl, creatinine clearance; CRNM, clinically relevant non-major; DAPT, dual antiplatelet therapy; DVT, deep vein thrombosis; INR, international normalized ratio; MI, myocardial infarction; OAC, oral anticoagulant; PCI, percutaneous coronary intervention; PE, pulmonary embolism; R, randomized; VKA, vitamin K antagonist.
Study Design
R
R
A Phase IV, Open-label, 2 x 2 Factorial, Randomized Controlled Study
Adapted from Lopes RD et al. Am Heart J. March 2018 doi:10.1016/j.ahj.2018.03.001 [Epub ahead of print]
ASA Placebo
R
*Dose reduced to 2.5 mg BID if patients meet 2 or more of the following criteria: age ≥ 80 years, weight ≤ 60 kg, or serum creatinine ≥ 1.5 mg/dL (133 µmol/L)
Randomization stratified by indication (ACS vs PCI)
AUGUSTUS trial
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Apixaban 5mg BID VKA (INR 2.0-3.0)
P2Y12 + Aspirin 81 mg/d P2Y12 + Aspirin 81 mg/d With ASA
P2Y12 + Aspirin placebo P2Y12 + Aspirin placebo Without ASA
R
2x2 Factorial design. 1:1:1:1 Randomization stratified by ACS vs PCI
Primary analysis: Apixaban vs VKA
Prim
ary
analy
sis:
Asp
irinvs p
lace
bo
NVAF Patients with ACS and/or
undergoing PCI stratified either
to medically treated (ACS
alone) or undergoing PCI
Study Design
AUGUSTUS trial
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Primary Outcome: Apixaban versus VKA ISTH major or CRNM bleeding
All patients were concomitantly receiving P2Y12 therapy
Lopes RD, Heizer G, Aronson R, et al. N Engl J Med. 2019;doi: 10.1056/NEJMoa1817083
VKA: 14.7%
Apixaban: 10.5%
HR 0.69, 95% CI 0.58–0.81P<0.001 for non-inferiorityP<0.001 for superiorityARR=4.2%NNT=24
AUGUSTUS trial
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Apixaban vs VKAPrimary Safety and Bleeding Outcomes
By anticoagulant regimen ApixabanN=2290
VKAN=2259
HR (95%CI)
ISTH major bleedingEvent rate per 100 patient-years
69 (3.0%)6.7
104 (4.6%)10.5
0.64 (0.4-0.86)
CRNM major bleedingEvent rate per 100 patient-years
180 (7.9%)18.2
246 (10.9%)26.1
0.69 (0.5-0.84)
GUSTO severe bleedEvent rate per 100 patient-years
5 (0.2%)0.5
8 (0.4%)0.8
0.59 (0.19-1.81)
GUSTO moderate bleedEvent rate per 100 patient-years
37 (1.6%)3.6
64 (2.8%)6.4
0.56 (0.37-0.84)
TIMI major or minor bleedEvent rate per 100 patient-years
96 (4.2%)9.5
132 (5.8%)13.5
0.70 (0.54-0.91)
GUSTO severe or moderate bleedEvent rate per 100 patient-years
41 (1.8%)4.0
68 (3.0%)6.8
0.58 (0.39-0.86)
TIMI major bleedEvent rate per 100 patient-years
TIMI minor bleedEvent rate per 100 patient-years
38 (1.7%)3.7
48 (2.1%)4.8
0.78 (0.5-1.20)
80 (3.5%)7.9
118 (5.2%)12.0
0.65 (0.49-0.86)
Intracranial hemorrhageEvent rate per 100 patient-years
5 (0.2%)0.5
13 (0.6%)1.3
0.39 (0.14-1.12)
Lopes RD, Heizer G, Aronson R, et al. N Engl J Med. 2019;doi: 10.1056/NEJMoa1817083
AUGUSTUS trial
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Primary Outcome: Aspirin versus Aspirin PlaceboISTH major or CRNM bleeding
Lopes RD, Heizer G, Aronson R, et al. N Engl J Med. 2019;doi: 10.1056/NEJMoa1817083
Placebo: 9.0%
Aspirin: 16.1%HR 1.89, 95% CI 1.59–2.24P<0.001ARI=7.1%NNH=14
All patients were concomitantly receiving P2Y12 therapy
AUGUSTUS trial
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Aspirin vs PlaceboPrimary Safety and Bleeding Outcomes
By antiplatelet regimen AspirinN=2277
PlaceboN=2279
HR (95%CI)
ISTH major bleedingEvent rate per 100 patient-years
108 (4.7%)11.1
65 (2.9%)6.5
1.70 (1.25-2.31)
CRNM major bleedingEvent rate per 100 patient-years
275 (12.1%)30.0
148 (6.5%)15.2
1.93 (1.58-2.36)
GUSTO severe bleedEvent rate per 100 patient-years
68 (3.0%)6.9
6 (0.3%)0.6
1.19 (0.40-3.53)
GUSTO moderate bleedEvent rate per 100 patient-years
7 (0.3%)0.7
37 (1.6%)3.7
1.73 (1.15-2.59)
TIMI major or minor bleedEvent rate per 100 patient-years
63 (2.8%)6.4
80 (3.5%)8.0
1.88 (.143-2.47)
GUSTO severe or moderate bleedEvent rate per 100 patient-years
40 (1.8%)4.0
1.72 (1.17-2.55)
TIMI major bleedEvent rate per 100 patient-years
TIMI minor bleedEvent rate per 100 patient-years
146 (6.4%)15.2
29 (1.3%)2.9
1.93 (1.23-3.03)
126 (5.5%)13.1
71 (3.1%)7.1
1.82 (1.36-2.44)
55 (2.4%)7.9
Intracranial hemorrhageEvent rate per 100 patient-years
8 (0.4%)0.8
10 (0.4%)1.0
0.82 (0.32-2.07)
Lopes RD, Heizer G, Aronson R, et al. N Engl J Med. 2019;doi: 10.1056/NEJMoa1817083
AUGUSTUS trial
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ISTH or CRNM Bleeding, According to Intervention Combination
All patients were concomitantly receiving P2Y12 therapy
Lopes RD, Heizer G, Aronson R, et al. N Engl J Med. 2019;doi: 10.1056/NEJMoa1817083
VKA + Aspirin (18.7%)
Apixaban + Aspirin (13.8%)
Apixaban + Placebo (7.3%)
VKA + Placebo (10.9%)
AUGUSTUS trial
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Secondary Endpoint: Apixaban vs VKADeath or Hospitalization
All patients were concomitantly receiving P2Y12 therapy
Lopes RD, Heizer G, Aronson R, et al. N Engl J Med. 2019;doi: 10.1056/NEJMoa1817083
Apixaban: 23.5%
VKA: 27.4%
HR 0.83, 95% CI 0.74–0.93P=0.002ARR=3.9%NNT=26
AUGUSTUS trial
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Secondary Endpoint: Aspirin vs Aspirin PlaceboDeath or Hospitalization
All patients were concomitantly receiving P2Y12 therapy
Lopes RD, Heizer G, Aronson R, et al. N Engl J Med. 2019;doi: 10.1056/NEJMoa1817083
Aspirin: 26.2%
Placebo: 24.7%
HR 1.08, 95% CI 0.96–1.21P=0.20
AUGUSTUS trial
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Ischemic Outcomes: Apixaban vs VKA
Endpoint Apixaban(N=2306)
VKA(N=2308)
Hazard Ratio(95%CI)
Death / Ischemic Events (%) 6.7 7.1 0.93 (0.75-1.16)
Death (%) 3.3 3.2 1.03 (0.75-1.42)
CV Death (%) 2.5 2.3 1.05 (0.72-1.52)
Stroke (%) 0.6 1.1 0.50 (0.26-0.97)
Myocardial Infarction (%) 3.1 3.5 0.89 (0.65-1.23)
Definite or Probable Stent Thrombosis (%)
0.6 0.8 0.77 (0.38-1.56)
Urgent Revascularization (%) 1.7 1.9 0.90 (0.59-1.38)
Hospitalization (%) 22.5 26.3 0.83 (0.74-0.93)
Lopes RD, Heizer G, Aronson R, et al. N Engl J Med. 2019;doi: 10.1056/NEJMoa1817083
All patients were concomitantly receiving P2Y12 therapy
AUGUSTUS trial
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Ischemic Outcomes: Aspirin vs Placebo
Endpoint Aspirin(N=2307)
placebo(N=2307)
Hazard Ratio(95%CI)
Death / Ischemic Events (%) 6.5 7.3 0.89 (0.71-1.11)
Death (%) 3.1 3.4 0.91 (0.66-1.26)
CV Death (%) 2.3 2.5 0.92 (0.63-1.33)
Stroke (%) 0.9 0.8 1.06 (0.56-1.98)
Myocardial Infarction (%) 2.9 3.6 0.81 (0.59-1.12)
Definite or Probable Stent Thrombosis (%)
0.5 0.9 0.52 (0.25-1.08)
Urgent Revascularization (%) 1.6 2.0 0.79 (0.51-1.21)
Hospitalization (%) 25.4 23.4 1.10 (0.98-1.24)
Lopes RD, Heizer G, Aronson R, et al. N Engl J Med. 2019;doi: 10.1056/NEJMoa1817083
All patients were concomitantly receiving P2Y12 therapy
AUGUSTUS trial
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Death or Hospitalization, According to Intervention Combination
All patients were concomitantly receiving P2Y12 therapy
Lopes RD, Heizer G, Aronson R, et al. N Engl J Med. 2019;doi: 10.1056/NEJMoa1817083
VKA + Placebo (27.3%)
Apixaban + Placebo (22.0%)
Apixaban + Aspirin (24.9%)
VKA + Aspirin (27.5%)
AUGUSTUS trial
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Antithrombotic Therapy in Patients With Atrial Fibrillation Treated With Oral Anticoagulation Undergoing Percutaneous Coronary Intervention A North American
Perspective–2018 Update; Angiolillo D.J. Circulation
?
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Bridging from oral to IV P2Y12 inhibitors
Angiolillo DJ et al. Circulation. 2017 Nov 14;136(20):1955-1975
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• There is no (strong) evidence
• ST is still the worst complication
(with the exception of ICH)
• It is not a matter of sum, it’s a matter of addends
Triple antithrombotic therapy is the right choice
VKA always loses
Aspirin may still play an imprtant role
Irreversible harm counts
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Triple antithrombotic therapy is the right choice
becuase 2 < 3
and
less is more less
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Background
1. Lopes RD et al. Am Heart J. March 2018 doi:10.1016/j.ahj.2018.03.001 [Epub ahead of print]2. Adapted from Lopes RD et al. Oral presentation at ACC Apr 2016; Chicago, IL, USA. Abstract number 695-153. Dewilde WJ et al. Lancet 2013;381:1107-1115
ACS, acute coronary syndrome; AF, atrial fibrillation; CAD, coronary artery disease; DAPT, dual antiplatelet therapy; OAC, oral anticoagulation; PCI, percutaneous coronary intervention; VKA, vitamin K antagonist.
▪ Atrial fibrillation (AF) is the most common cardiac arrhythmia, with increasing prevalence among the elderly.
▪ Approximately 20 to 30% of patients with AF also have concomitant coronary artery disease (CAD) and 5 to 10% of patients who undergo percutaneous coronary intervention (PCI) have AF.
▪ The WOEST trial3 in patients undergoing PCI on a VKA showed that the use of clopidogrel without aspirin was associated with significantly fewer bleeding events than the use of DAPT without an apparent increase in ischemic events.
▪ The WOEST trial3 challenged the accepted paradigm that aspirin must be a cornerstone of therapy in patients with concomitant AF and CAD.
▪ Current guidelines (based mainly on expert consensus) recommend the choice and duration of triple therapy depends on patient bleeding risk, stroke risk, and clinical presentation (ACS or elective PCI).
➢ A clinical conundrum arises when patients with AF on oral anticoagulation (OAC) develop an acute coronary syndrome (ACS) and/or require PCI.
➢ VKAs have not been shown to prevent stent thrombosis and are not indicated for secondary prevention following an ACS, whereas DAPT does not provide a large treatment effect in preventing AF-related strokes.
➢ Triple therapy significantly increases the risk of bleeding and there is a significant unmet need for an oral antithrombotic strategy with an acceptable benefit/risk profile for treating patients with both AF and CAD. Major Bleeding
DAPT OAC+
Stent Thrombosis Stroke
How can you simultaneously prevent all three?2
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Background
▪ These trials were not powered or designed to assess whether the bleeding reduction was due to the use of a NOAC or the removal of aspirin from the post-PCI oral antithrombotic strategy.1
▪ Triple therapy with NOAC has never been investigated
1. Lopes RD et al. Am Heart J. March 2018 doi:10.1016/j.ahj.2018.03.001 [Epub ahead of print]2. Adapted from Gibson CM et al. N Engl J. Med. 2016;375:2423-24343. Adapted from Cannon CP et al. N Engl J. Med. 2017;377:1513-1524
≠ The licensed dose of Rivaroxaban for the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors is 20 mg OD† Dabigatran 110 mg BID is not a licensed dose in the US
AF, atrial fibrillation; ASA, aspirin; CRNM, clinically relevant non major; DAPT, dual antiplatelet therapy; NOAC, non-vitamin K antagonist oral anticoagulant; PCI, percutaneous coronary intervention; VKA, vitamin K antagonist.
PIONEER AF-PCI2 RE-DUAL PCI3
NVAF who
had
undergone
PCI with
stenting
N = 21241:1:1
Rivaroxaban 15 mg OD≠ + P2Y12inhibitor for 12 months
Rivaroxaban 2.5 mg BID≠ + DAPT* for 1, 6, 12 months
VKA + DAPT* for 1, 6, 12 months
N = 2725Warfarin + P2Y12 inhibitor + ASA
for 1 to 3 months
Dabigatran 110 mg BID†
+ P2Y12
Dabigatran 150 mg BID + P2Y12
R
AF who had
undergone
PCI
R
In patients where DAPT (ASA + P2Y12) was received for < 12 months SAPT (ASA) was given instead
In PIONEER AF-PCI2 P2Y12 = clopidogrel, prasugrel, or ticagrelor
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▪ PIONEER AF-PCI trial provided a clear signal of fewer bleeding events in regimens including rivaroxaban, whilst the efficacy
outcome (death from cardiovascular causes, MI, and stroke) occurred at similar rates among treatment arms. This bleeding
reduction was observed using doses of rivaroxaban that have not demonstrated proven efficacy in stroke reduction among
patients with AF. This study was not powered for efficacy and effects on ischemic events.
▪ RE-DUAL PCI trial demonstrated a reduction in bleeding in the NOAC arms compared with the traditional VKA based triple
therapy arm. However, RE-DUAL PCI was unable to provide insight into whether the reduction in bleeding in the dabigatran
based arms was due to dabigatran or the removal of aspirin.
▪ Two other trials of antithrombotic therapy strategy among patients with AF requiring DAPT are ongoing:
➢ ENTRUST-AF PCI trial will randomize 1500 patients with a history of AF to an edoxaban-based strategy or VKA on top of
aspirin and a P2Y12 inhibitor. The study will enroll patients outside the US and results are expected in 2019.
➢ SAFE A will randomize 600 patients with AF undergoing PCI with a drug-eluting stent to 1-month or 6-months of P2Y12
inhibitor therapy on background apixaban and aspirin, providing guidance on the optimal duration of an apixaban-based
triple therapy regimen. The primary outcome for both trials will be ISTH major or CRNM bleeding at 1 year.
▪ PIONEER AF-PCI and RE-DUAL PCI provided important randomized data where prior experience was limited. AUGUSTUS
will extend the findings of those trials and will be the first large randomized study to test the WOEST strategy to distinguish
the bleeding contributions of apixaban and the removal of aspirin. The trial will provide unique information that will inform
physicians and guidelines on the optimal antithrombotic strategy in these high-risk patients across the spectrum of CAD.
AF, atrial fibrillation; CAD, coronary artery disease; CRNM, clinically relevant non-major; DAPT, dual antiplatelet therapy; ISTH, International Society on Thrombosis and Haemostasis; MI, myocardial infarction; NOAC, non-vitamin K antagonist oral anticoagulant; PCI, percutaneous coronary intervention; VKA, vitamin K antagonist.
Lopes RD et al. Am Heart J. March 2018 doi:10.1016/j.ahj.2018.03.001 [Epub ahead of print]
Background
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▪ Pivotal NOAC trials in AF excluded patients needing DAPT, while DAPT trials following acute MI and/or PCI excluded
patients on oral anticoagulation.
▪ AUGUSTUS will help answer important questions about patients with AF and CAD and has some unique features:
➢ It is the largest study in the field, including the whole spectrum of patients with CAD (ACS with/without PCI, elective PCI).
➢ The apixaban dose (5 mg twice daily) used in AUGUSTUS has proven efficacy in stroke prevention in AF.
➢ The unique 2 x 2 factorial design will provide insight into whether aspirin may (or may not) be dropped in patients with AF
and CAD receiving OAC plus a P2Y12 inhibitor.
➢ Unlike PIONEER AF-PCI and RE-DUAL PCI, AUGUSTUS does not exclude patients with a history of prior stroke,
transient ischemic attack, prior gastrointestinal bleeding, or anemia.
➢ The 6 month follow-up will delineate bleeding and ischemic events in the highest-risk time period following the index
event. Guidelines recommend DAPT in stable ischemic patients treated with DES for 6 months only, so patients will not
be subjected to prolonged DAPT used with prior generation DESs. The 14 days window between index event (ACS
and/or PCI) and randomization allows more time for patients to be treated with any antithrombotic strategy until they are
stable.
▪ AUGUSTUS will include both patients with new onset AF as well as those already on a stable anticoagulant regimen.
▪ Apixaban 5 mg twice daily was chosen due to proven efficacy for stroke reduction compared with warfarin in patients with
AF. This dose was associated with increased bleeding in APPRAISE-2 however the comparator was placebo not warfarin.
Lopes RD et al. Am Heart J. March 2018 doi:10.1016/j.ahj.2018.03.001 [Epub ahead of print]
ACS, acute coronary syndrome; AF, atrial fibrillation; CAD, coronary artery disease; DAPT, dual antiplatelet therapy; DES, drug eluting stent; INR, international normalized ratio; MI, myocardial infarction; NOAC, non-vitamin K antagonist oral anticoagulant; OAC, oral anticoagulant; PCI, percutaneous coronary intervention; VKA, vitamin K antagonist.
Background
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AUGUSTUS – Research Hypothesis
Two Independent Hypotheses:
Apixaban is at least non-inferior or superior to VKA on the composite outcome of ISTH major bleeding or clinically
relevant non-major (CRNM) bleeding in patients with NVAF who develop ACS and/or require PCI with concomitant
antiplatelet therapy P2Y12 with or without aspirin.
Single antiplatelet therapy with a P2Y12 inhibitor is superior to dual antiplatelet therapy with a P2Y12 inhibitor and
aspirin on the combined outcome of ISTH major bleeding or clinically relevant non-major bleeding in patients with
NVAF with a recent ACS and/or require PCI with concomitant anticoagulant therapy.
Lopes RD, Heizer G, Aronson R, et al. N Engl J Med. 2019;doi: 10.1056/NEJMoa1817083
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AUGUSTUS – Outcomes
Primary Outcome:
• First occurrence of ISTH major or CRNM bleeding
Secondary Outcomes:
• First occurrence of the composite of all-cause death and all-cause hospitalization
• First occurrence of the composite endpoint of death and ischemic events (stroke, MI, stent thrombosis, urgent
revascularization)
Lopes RD, Heizer G, Aronson R, et al. N Engl J Med. 2019;doi: 10.1056/NEJMoa1817083
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Statistical Analysis—Hierarchical Testing
NI = non-inferiority; Sup = superiority Lopes RD, et al. Am Heart J. 2018;200:17-23.
Placebo vs. Aspirin:
Major / CRNM BleedingSup
Death / HospitalizationSup
Death / Ischemic EventsSup
Apixaban vs. VKA:
Major / CRNM BleedingNI then Sup
Death / HospitalizationSup
Death / Ischemic EventsSup
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Participating Countries and corresponding Number of Patients
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Total (N=4614)
Age, median (25th, 75th), years 70.7 (64.2, 77.2)
Female, % 29.0
CHA2DS2-VASc score, mean (SD) 3.9 (1.6)
HAS-BLED score, mean (SD) 2.9 (0.9)
Prior OAC, % 49.0
P2Y12 inhibitor, %
Clopidogrel 92.6
Prasugrel 1.1
Ticagrelor 6.2
Number of days from ACS/PCI to
randomization, mean (SD)6.6 (4.2)
Qualifying index event, %
ACS and PCI 37.3
ACS and no PCI 23.9
Elective PCI 38.8
Baseline Characteristics
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Total Randomized
N=4614
Randomized to ApixabanN=2306
Randomized to VKA
N=2308
Randomized to AspirinN=2307
Randomized to PlaceboN=2307
Study Drug Discontinuation
291 (12.6%) 311 (13.5%) 385 (16.7%) 337 (14.6%)
Lost to Follow-up
6 (0.3%) 7 (0.3%) 5 (0.2%) 8 (0.3%)
Withdrawal of Consent
29 (1.3%) 46 (2.0%) 43 (1.9%) 30 (1.3%)
OAC Aspirin/Placebo
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AUGUSTUS – Summary
• ISTH Major / Clinically Relevant Non-major Bleeding
31% lower with apixaban than VKA
89% higher with aspirin than placebo (47% lower with placebo than aspirin)
• Death / Hospitalization
17% lower with apixaban than VKA
Similar between aspirin and placebo
• Death / Ischemic Events
Similar rate between apixaban and VKA
Similar rate between aspirin and placebo
Lopes RD, Heizer G, Aronson R, et al. N Engl J Med. 2019;doi: 10.1056/NEJMoa1817083
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• Compared to VKA regimens (VKA plus a P2Y12 inhibitor with or without aspirin),
apixaban regimens (apixaban plus a P2Y12 inhibitor with or without aspirin) showed
significantly less bleeding and fewer deaths or hospitalizations with a similar rate of death
or ischemic events in patients with NVAF and recent ACS and/or undergoing PCI.
• Compared to no aspirin regimens (P2Y12 inhibitor plus an anticoagulant), regimens with
aspirin plus a P2Y12 inhibitor and anticoagulant showed significantly more bleeding and
similar rates of death or hospitalizations and death or ischemic events in patients with
NVAF and recent ACS and/or undergoing PCI.
AUGUSTUS – Conclusion
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Conclusioni (personali)• La triplice terapia aumenta i sanguinamenti
• Il beneficio maggiore (in termini di morte e ospedalizzazioni) viene conferito dalla scelta di apixaban vs warfarin e non dalla sospensione di aspirina
• Può essere ragionevole mantenere una triplice terapia con apixaban a dosaggio pieno per 1-3 mesi dopo PCI dopo attenta valutazione del rischio ischemico ed emorragico
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Triple antithrombotic therapy is the right choice
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Triple antithrombotic therapy is the right choice
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CE mark indication for RESOLUTE
1-month DAPT
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RESOLUTE:
Risk of ST in Patients Interrupting DAPT Beyond One Month
Patients who completed follow-up beyond one year had no additional ST events one-year post-interruption. (R-China, R-Japan SVS, R-Asia and R-US 38 mm have not completed follow-up beyond one year and will be included in future analyses.)
4240 182 949
35 6 14
NA 3 250
Patients at risk
No. of events
Median days to
interruption
1 p < 0.05 for comparison to Never Interrupted group. Post-hoc RESOLUTE Pooled DAPT analysis was not powered for the analysis shown.2 Including patients with no DAPT interruption except for ST while on DAPT through 12 months314-day cutoff selected because studies have shown that it takes up to 14 days for the platelet function to recover after DAPT withdrawal.4 Patient with a history of thrombosis was on DAPT at the time of ST event but had interrupted DAPT for two consecutive days prior to the event.
ESC guidelines recommend DAPT duration of 6–12 months after DES implantation in all patients and one year after ACS, irrespective of the type of implanted stent.
949 783 627
1 0 0
250 271 288
Interruption duration > 1 day
Su
bse
qu
ent
ST
(AR
C D
ef/P
rob
) (%
)
0.83
3.301
0.111 0.00.00.11
Interrupted 1−12 moInterruption duration breakout
Timing of First DAPT Interruption and ST Through 1 Year
32
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XIENCE - 0% Stent Thrombosis with DAPT
Interruption after 3 Months
XIENCE - 0% Stent Thrombosis with DAPT
Interruption after 3 Months
Source: Derived from Palmerini, T. PCR 2012.
• Pooled data of 10,615
patients from four real-
world trials:
– XIENCE V USA (n=6,516)
– SPIRIT V (n=1,662)
– SPIRIT Women SAS
(n=1,506)
– XIENCE V India (n=931)
• 919 patients interrupted
DAPT between 3 to 12
months with 0% ST
• Definition of
DAPT Interruption: either
aspirin and/or
thienopyridine not taken
for at least 1 day for any
reason
XIENCE - 0% Stent Thrombosis Rate After DAPT
Interruption from 3 to 12 Months
*Including patients with no DAPT interruption except possibly after ST through 365 days
XIENCE shows good safety outcomes
even when DAPT is interrupted after 3 months
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|
Primary Endpoint: Total number of TIMI bleeding events WOEST
Days
Cum
ula
tive
incid
en
ce
of b
lee
din
g
0 30 60 90 120 180 270 365
0 %
10 %
20 %
30 %
40 %
50 %
284 210 194 186 181 173 159 140n at risk: 279 253 244 241 241 236 226 208
Triple therapy group
Double therapy group
44.9%
19.5%
p<0.001
HR=0.36 95%CI[0.26-0.50]
Lancet 2013;381:1107-15.
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Secondary Endpoint (Death, MI,TVR, Stroke, ST)WOEST
Days
Cum
ula
tive
incid
en
ce
0 30 60 90 120 180 270 365
0 %
5 %
10 %
15 %
20 %
284 272 270 266 261 252 242 223n at risk: 279 276 273 270 266 263 258 234
17.7%
11.3%
p=0.025
HR=0.60 95%CI[0.38-0.94]
Triple therapy groupDouble therapy group
Lancet 2013;381:1107-15.
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• Open-label design
• Definition of bleeding: it was sufficient to repeat blood tests
• “Underpowered” to assess ischemic events
• Patients with history of prior stroke or TIA were excluded
• No data on procedural features
• Selection bias? The trial enrolled 5 pts per Center in 3 yrs
• The main inclusion criterion was documented AF that occurred within 1 year before screening (1 pt out of 2 had paroxismal AF)
• Up to 30% of pts permanently discontinued the treatment before the scheduled termination date
• 1 out of 2 pts in the triple Tx groups were assigned to DAPT for 12 mo
PIONEER Main limitations
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REDUAL PCI: safety end points
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Eur Heart J. 2018;39(31):2847-2850
Triple antithrombotic therapy is the right choice
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NAO and antiplatelets
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NAO and antiplatelets : apixaban
Alexander JH et al. Eur Heart J 2014;35:224-32
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Circulation. 2013;127:634-640
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Tasso di sanguinamento di edoxaban e warfarinin base alla terapia antipiastrinica
Xu H et al. J Am Heart Assoc. 2016;5: e002587 doi: 10.1161/JAHA.115.002587.*Pazienti trattati con edoxaban 30 mg con peso ≤60 kg, compromissione moderatadella funzionalità renale o uso concomitante di inibitori della P-gp.
1,18
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Usereste mai 2,5 x 2 per FA???? (slide su basse dosi)
Pioneer riduce eventi se aggiustamento dose, ma cosa fare per quelli che
avrebbero diritto a 10 mg???
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66
Antithrombotic Therapy in Patients With Atrial Fibrillation Treated With Oral Anticoagulation Undergoing Percutaneous Coronary Intervention A North American
Perspective–2018 Update; Angiolillo D.J. CIrculation
Figure 2. Management of antiplatelet therapy in patients with atrial fibrillation undergoing percutaneous coronary intervention
(PCI) treated with an oral anticoagulant (OAC): 2018 North American expert consensus update.
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Danish Registry: ischemic and bleeding events
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Danish Registry: Early and late hazards of bleeding events
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0
2
4
6
8
10
12
ISAR MATTIS
Coumadin
ASA+Ticlo
ASA
n:517 n:350 n:1653n:485
MA
CE
(%
)
Ticlopidine during PCI with use of Coronary Stents
- Schomig et al, N Engl J Med 1996 - Bertrand et al, Circulation 1998
- Urban et al, Circulation 1998 - Leon et al, N Engl J Med 1998
FANTASTIC STARS
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Safety of aspirin, clopidogrel, and warfarin after
coronary stenting
0
5
10
15
20
25
30
35
40
45
FA Valve
prosthesis
LV
aneurysm
LV
thrombus
CV
accident
other bleeding
event
9,2%
Orford J Am Heart J 2004;147:463–7
Dipartimento Cardiovascolare
Clinico e di RicercaOspedali Riuniti
Bergamo
Dipartimento Cardiovascolare
Clinico e di RicercaOspedali Riuniti
Bergamo
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64 66 65
83
36 34 35
17
0
20
40
60
80
100
Australia/New
Zeland/Canada
Europe Argentina/Brazil USA
warfarin/dual antiplatelet warfarin/single antiplatelet
Geografical variations in combination
regimen at discharge
P<0.001%
Dipartimento Cardiovascolare
Clinico e di RicercaOspedali Riuniti
Bergamo
Dipartimento Cardiovascolare
Clinico e di RicercaOspedali Riuniti
Bergamo
The GRACE Investigators. Eur Heart J 2007;28:1717-1722
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OAC + single antiplatelet vs triple therapy
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77
Antithrombotic Therapy in Patients With Atrial Fibrillation Treated With Oral Anticoagulation Undergoing Percutaneous Coronary Intervention A North American
Perspective–2018 Update; Angiolillo D.J. CIrculation
Figure 2. Management of antiplatelet therapy in patients with atrial fibrillation undergoing percutaneous coronary intervention
(PCI) treated with an oral anticoagulant (OAC): 2018 North American expert consensus update.
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2018 ESC/EACTS Guidelines on myocardial revascularization The Task Force on myocardial revascularization of the European Society of Cardiology (ESC) and European Association for
Cardio-Thoracic Surgery (EACTS); Neumann FJ et al. European Heart Journal (2018) 00, 1–96
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79
Antithrombotic Therapy in Patients With Atrial Fibrillation Treated With Oral Anticoagulation Undergoing Percutaneous Coronary Intervention A North American
Perspective–2018 Update; Angiolillo D.J. CIrculation
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Bleeding Cumulative Distribution
“Double” vs “Triple” TX
100
90
80
70
60
50
0 200 300 450 600
%
Days
Ble
edin
g e
vent fr
ee s
urv
ival 95.1 %
89.2 %
P=0.13
Double therapy (ASA + Clopidogrel)
Triple therapy (ASA + Clopidogrel + Warfarin)
Rossini, et al. Am J Cardiol 2008
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Bleeding Cumulative Distribution by INR
“Double” vs “Triple” TX
Rossini, et al. Am J Cardiol 2008
100
90
80
70
60
50
0 200 300 450 600
%
Double therapy
Triple therapy with INR < 2.6
95.1 %
95.1 %
Days
Ble
edin
g e
vent fr
ee s
urv
ival
Triple therapy with INR ≥ 2.6
66.7 %
†
‡
† P<0.0001 vs Double therapy
‡ P<0.0001 vs Triple with INR <2.6
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0
20
40
60
80
100
OR=89.8
(29.9-270)
HR=19.2
(5.6-65.5)
OR=4.8
(2.0-11.1)
HR=13.7
(4.0-46.7)
Odds/
Haza
rd R
ati
o
Iakovou et al
JAMA 2005
Park et al
Am J CARD 2006
Kuchulakanti et al
Circulation 2006
Airoldi et al
Circulation 2006
Premature Discontinuation of Antiplatelet Therapy as Predictor of ST
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Mort
alit
y
%
Discontinued
Continued
1 2 3 4 5 6 7 8 9 10 11 120
5
10
15
p<0.001
Months
Discontinuation of Thienopyridine after DES
PREMIER Registry: 500 DES treated MI pts
Spertus et al, Circulation 2006;113:2803-2809
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Stone G. TCT 2011
Mega-Meta Analysis XIENCE shows no signal for increased risk of ST from 3 months to 2 years
Interrupted
on or before
1 month
Interrupted
between
1 and 3 months
Interrupted
between
3 and 6 months
Interrupted
between
6 and 12 months
Never Interrupted
through 2-year
study period
Interrupted
between
1 and 2 years
0
1
2
3
ST
thro
ugh
2 Y
ears
(%
)P= 0.04 P= 0.13 P= 0.33P= 0.34P<0.0001
0.63
2.55
2.11
1.38
0.88
0.44
P values vs. never
interrupted
#ST=44 #ST=13 #ST=3 #ST=4 #ST=11 #ST=8
With XIENCE, “DAPT interruption did not result in stent thrombosis in 99.4% of the patients.”
Median # days
off DAPT (IQR)
482.5
(19, 668)
287
(103.5, 351)
374
(8, 731)
379
(365, 481)
518
(59, 566)
0
(0, 0)
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Key points
• Clinical events: ST vs ST-unrelated ischemic events
• Power of the studies and length of discontinuation
• Median time from PCI to DAPT
• Type of discontinuation: single vs dual
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J Am Coll Cardiol Intv 2011;4:1298-309
XIENCE V USA:
Stent thrombosis and interruption of DAPT
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Mehran RM et al. Eur Heart J 2009 June ; 30: 1457-1466
Cox model adjusted for 36 baseline predictors, with MI and major
bleeding (non-CABG) as time-updated covariates
Of 13,819 enrolled pts, 524 (3.8%) died within 1 year
Myocardial infarction 3.1 (2.4-3.9) <0.001
Major bleeding 3.5 (2.7-4.4) <0.001
Blood transfusion 4.5 (3.4-5.9) <0.001
HR ± 95% CI P-valueHR (95% CI)
Influence of Major Bleeding and MI within 30 Days
on Risk of Death Over 1 Year
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Major bleeding
No major bleeding
%
Antiplatelet Discontinuation
Major Bleeding and Antiplatelet Discontinuation
G. Musumeci, R. Rossini, C. Lettieri et al Cath Card Interv 2011 Nov 22.[Epub ahead of print]
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%
Minor bleeding
No bleeding
P<0.001P=0.001
Minor Bleeding and Long-Term Outcome
G. Musumeci, R. Rossini, C. Lettieri et al Cath Card Interv 2011 Nov 22.[Epub ahead of print]