Pacientes con FA que sufren un SCA y son sometidos a intervención coronaria percutánea. Guías y preguntas abiertas

Novedades en el manejo del paciente con FA: actualización tras AHA 2016
Pacientes con FA que sufren un SCA
y son sometidos a intervención
coronaria percutánea:
guías y preguntas abiertas
Antonio Fernández-Ortiz
Hospital Clínico San Carlos

AF and PCI
 Background and epidemiology
 Current guidelines for management
 Gaps in evidence ( i.e NOACs)
 Rationale and design PIONEER

@ 1 Billion people in US and Europe
@ 20 Million with AF (1-2% of population)1,2
@ 16 Million anticoagulation indicated (80%) 1,2
@ 4.8 Million have CAD as well (20%-45%)1,2
@ 1- 2 Million potential revasc (20%-25%) 3,4
1. The AFFIRM Investigators. Am Heart J 2002;143:991–1001;
2. Carpodanno D et al, Circ Cardiovasc Interv 2014;7:113–124;
3. Kralev S et al, PLoS One 2011;6:e24964;
4. Bahit MC et al, Int J Cardiol 2013;170:215–220
AF and CAD often occur together because of the strong association
of both conditions with aging and overlapping risk factors
24.9% of patients with AF enrolled in ARISTOTLE had prior PCI4
Gibson et al. AHA 2016
Epidemiology: AF and PCI

Atrial Fibrillation (ACTIVE W)1: The
combination of aspirin and clopidogrel is not as
effective as warfarin in patients with AF1
However
Stenting (STARS)2: The combination of
aspirin and a thienopyridine is more effective
than warfarin in patients with coronary stents 2
1. Lancet 2006 Jun 10;367(9526):1903-12. 2. N Eng J Med 1998 Dec 3;339(23):1665-71.
The Optimal Management of AF and ACS Differ
Gibson et al. AHA 2016

2007 Guidelines recommended
Prolonged Triple Therapy
ACC/AHA 2007 Guidelines for management of patients with NSTE-ACS
UA/NSTEMI patient groups at
discharge with indication for
anticoagulation
Bare-metal stent group
ASA*
 162–325 mg/day for at least 1 month, then 75–
162 mg/day indefinitely
Clopidogrel#
 75 mg/day for at least 1 month and ideally up
to 1 year
Warfarin‡
 When added to ASA plus clopidogrel an INR of
2.0–2.5 is recommended
Drug-eluting stent group
ASA*
 162–325 mg/day for at least 3–6 months,
then 75–162 mg/day indefinitely
Clopidogrel#
 75 mg/day for at least 1 year
Warfarin‡
 When added to ASA plus clopidogrel an INR of
2.0–2.5 is recommended
*For ASA allergic patients, use clopidogrel alone (indefinitely), or try desensitization; #for clopidogrel allergic patients, use ticlopidine 250 mg by mouth twice
daily; ‡continue ASA indefinitely and warfarin longer term as indicated for specific conditions such as AF
Anderson JL et al, Circulation 2007;116:e148–e304

Crudeincidencerates
(eventsper100person-years±SE)
CV death plus MI plus
ischaemic stroke
Fatal and
non-fatal bleeding
0
10
20
30
40
Triple therapy (VKA plus ASA plus clopidogrel)
VKA plus single antiplatelet therapy
DAPT (ASA plus clopidogrel)
VKA monotherapy
Single antiplatelet therapy
Triple Therapy with a VKA Reduces Thromboembolic
Events but Increases Bleeding after PCI in AF Patients
Danish registry data (2000–2009; N=11,480 patients)
Lamberts M et al, Circulation 2012;126:1185–1193

Kirchhof P, et al. 2016 ESC Guidelines for the management of AF. EHJ doi:10.1093/eurheartj/ehw210
2016 ESC/EHRA/ESO Guidelines for AF

2016 ESC/EHRA/ESO Guidelines for AF

AF and PCI: gaps in evidence
 NOAC lowest effective dose for stroke prevention?
 Omission of aspirin while maintaining a P2Y12 inh.?
 Safety of tica/prasu as part of combination therapy?
 Duration of triple/dual combination therapy?

Dose of Rivaroxaban Varies in ACS &
Atrial Fibrillation Patients
ACS/
Stenting
Atrial
Fibrillation
Stent
+
Afib
DAPT +
2.5 mg BID Riva Riva 20 mg QD
4 Fold Difference in Riva Dose Between ACS and AF
1. Schmitt J et al Atrial fibrillation in acute myocardial infarction: a systematic review of the
incidence, clinical features and prognostic implications. Eur Heart J 2009;30:1038–1045. Gibson et al. AHA 2016

Patient populations Supporting evidence
Patients with moderate
renal impairment
(CrCl 30-49 ml/min)
ROCKET-AF1
n=1,474

XANTUS2
n=1,410

PMSS3
n=6,034*

Japanese patients
J-ROCKET4
n=639

XAPASS5
n=4,909

Patients undergoing PCI#
PIONEER AF-PCI6
n=696

1. Fox KAA et al, Eur Heart J 2011;32:2387–2394; 2. Camm AJ et al, Eur Heart J 2016;37:1145–1153
3. Tamayo S et al. Circulation. 2015 (132 Suppl 3); 4. Hori M et al. Circ J 2012; 76: 2104 – 2111
5. Ikeda T et al, presented at ESC 2016: 2953. Available at: http://congress365.escardio.org
6. Gibson CM et al, New Engl J Med 2016; doi: 10.1056/NEJMoa1611594
*Patients with renal dysfunction (as surrogate)
#The tested dosing regimens with rivaroxaban in PIONEER AF-PCI are currently not approved
The reduced dose of Rivaroxaban 15 mg OD was
also studied in the Phase IIIb RCT J-ROCKET AF

Per-protocol population on-treatment; The study was not powered to test efficacy hypotheses
Hori M et al, Circ J 2012;76:2104–2111
Endpoints HR 95% CI HR (95% CI) p-value
Principal Safety Outcome
Major or non-major
clinically relevant bleeding
1.11 0.87–1.42
<0.001
(non-inferiority)
Major bleeding 0.85 0.50–1.43 N.S.
Non-major clinically
relevant bleeding
1.20 0.92–1.56 N.S.
Primary Efficacy Endpoint
Stroke/Systemic Embolism 0.49 0.24–1.00 0.050
All cause stroke 0.46 0.22–0.98
Not reportedPrimary hemorrhagic stroke 0.73 0.16–3.25
Primary ischemic stroke 0.40 0.17–0.96
0,1 1 10
Rivaroxaban 15 mg OD in the
Phase IIIb RCT J-ROCKET AF

Per-protocol population on-treatment; Analysis method: Cox proportional hazard model
Hori M et al, Circ J 2012;76:2104–2111
Number of patients at risk:
Rivaroxaban 637 593 563 542 443 313 217 156 48 0
Warfarin 637 581 547 517 406 285 212 154 48 0
Rivaroxaban 15 mg OD in the
Phase IIIb RCT J-ROCKET AF
Event rate (%/year) Rivaroxaban Warfarin
Stroke/SE 1.26 2.61
Days since randomization
Cumulativeeventrate
timetofirstevent(%)
0 100 200 300 400 500 600 700 800 900
Warfarin
HR=0.49 (95% CI 0.24–1.00)
p=0.050 (two-sided test)
Rivaroxaban
0
1
2
3
4
5
6
7

• Small-scale, open-label WOEST study (N=573) compared safety outcomes with triple
therapy (VKA plus clopidogrel plus ASA) vs dual therapy (VKA plus clopidogrel): 69%
of WOEST patients had AF
0
10
20
30
40
50
Any bleeding TIMI major TIMI major +
minor
Cumulativeincidence(%)
*
*
*p<0.05
Dewilde WJ et al, Lancet 2013;381:1107–1115
Use of dual therapy was associated with significantly lower rates of bleeding
and overall mortality vs triple therapy, with similar rates of thrombotic events
*
0
10
20
30
40
50
Death MI Stroke
Cumulativeincidence(%)
Safety outcomes Efficacy outcomes
VKA plus clopidogrel (dual
therapy) (n=279)
VKA plus clopidogrel plus ASA
(triple therapy) (n=284)
23% 14% 31%
Power
The WOEST trial:
is ASA necessary in triple therapy?

1. Kirchhof P et al, Eur Heart J 2016; doi:10.1093/eurheartj/ehw210; 2. Amsterdam EA et al, Circulation 2014;130:e344–e426;
3. Sørensen R et al, Lancet 2009;374:1967–1974; 4. Gibson CM et al, Am Heart J 2015;169:472–478e5
PIONEER AF-PCI
Study Rationale and Objective
Rationale
Objective
 Patients with AF after PCI are indicated for both oral
anticoagulation and antiplatelet therapy1,2
 However, combining a VKA with antiplatelet therapy is associated
with an increased risk of serious bleeding episodes3
 There is currently a lack of evidence to support clinical guidelines
 To assess the safety of two rivaroxaban treatment strategies
compared with the current standard of care in patients with
paroxysmal, persistent or permanent NVAF undergoing PCI with
stent placement4

*CrCl 30–49 ml/min: 10 mg OD; #first dose 72–96 hours after sheath removal; ‡clopidogrel (75 mg daily)
(alternative use of prasugrel or ticagrelor allowed, but capped at 15%); §ASA (75–100 mg daily) plus clopidogrel (75 mg daily)
(alternative use of prasugrel or ticagrelor allowed, but capped at 15%); ¶first dose 12–72 hours after sheath removal
1. Janssen Scientific Affairs, LLC. 2016. https://clinicaltrials.gov/ct2/show/NCT01830543 [accessed 10 Oct 2016];
2. Gibson CM et al, Am Heart J 2015;169:472–478e5; 3. Gibson CM et al, New Engl J Med 2016; doi: 10.1056/NEJMoa1611594
An open-label, randomized, controlled phase IIIb safety study
Rivaroxaban 15 mg OD*# plus single antiplatelet‡
End of treatment
(12 months)
Rivaroxaban 2.5 mg BID#
plus DAPT§
VKA (INR 2.0–3.0)¶
plus DAPT§
Rivaroxaban 15 mg OD*
plus low-dose ASA
VKA plus low-dose ASA
N=2,124
1:1:1
Population:
patients with
paroxysmal,
persistent or
permanent NVAF
undergoing PCI
(with stent
placement)
R
Decision for
DAPT
duration: 1,
6 or 12
months
DAPT duration
(1 or 6 months)
PIONEER AF-PCI
Study design

1. Dewilde WJ et al, Lancet 2013;381:1107–1115; 2. Amsterdam EA et al, Circulation 2014;130:e344–e426;
3. O’Gara PT et al, J Am Coll Cardiol 2013;61:e78–e140; 4. Kirchhof P et al, Eur Heart J 2016; doi:10.1093/eurheartj/ehw210;
5. Heidbuchel H et al, Europace 2015;17:1467–1507
PIONEER AF-PCI
Rationale for Dual and Triple Therapy Arms
Study group 1 Study group 2 Study group 3
Rivaroxaban 15 mg OD
plus P2Y12
Rivaroxaban
2.5 mg BID
plus ASA plus
P2Y12
Rivaroxaban
15 mg OD
plus ASA
VKA plus ASA
plus P2Y12
VKA plus ASA
Where US guidelines
recommend triple therapy
with a VKA,2,3 recent
European guidelines suggest
that a NOAC may be used in
triple and dual therapy after
PCI4,5
Triple therapy with a VKA plus
DAPT followed by dual therapy
with VKA plus ASA is the
standard of care for patients
with AF and ACS, as
recommended by
US guidelines2,3
The WOEST study showed oral
anticoagulation in combination
with clopidogrel was associated
with significantly lower bleeding
than triple therapy with no
increase in thrombotic events1
This strategy has not yet been
tested in a large study
12 months 1, 6 or 12 months Up to 12 months 1, 6 or 12 months Up to 12 months

PIONEER AF-PCI
Rationale for Anticoagulant Dose Selection
plus P2Y12
Rivaroxaban
2.5 mg BID
plus ASA plus
P2Y12
Rivaroxaban
15 mg OD
plus ASA
VKA plus ASA
plus P2Y12
VKA plus ASA
The safety of the rivaroxaban
2.5 mg BID dose in combination
with DAPT was demonstrated in
the
ATLAS ACS 2 TIMI 51 trial3
A target INR of 2.0–3.0 was
selected because this is the
recommended INR for stroke
prevention in patients with AF4
ATLAS ACS TIMI 46: rivaroxaban
15 mg OD was associated with
lower bleeding rates than 20 mg
OD when taken in combination
with antiplatelets1
J-ROCKET AF: rivaroxaban
15 mg OD showed similar
efficacy and safety compared
with warfarin, with a trend
towards a lower incidence of
stroke/SE2
1. Mega JL et al, Lancet 2009;374:29–38; 2. Hori M et al, Circ J 2012;76:2104–2111;
3. Mega JL et al, N Engl J Med 2012;366:9–19; 4. Kirchhof P et al, Eur Heart J 2016; doi:10.1093/eurheartj/ehw210

PIONEER AF-PCI
Rationale for Selection of ASA or P2Y12 Inhibitor
plus P2Y12
Rivaroxaban
2.5 mg BID
plus ASA plus
P2Y12
Rivaroxaban
15 mg OD
plus ASA
VKA plus ASA
plus P2Y12
VKA plus ASA
In Groups 2 and 3, a period of triple therapy was followed by dual
therapy using an OAC plus low-dose ASA.
ASA was selected over clopidogrel because it is used for long-term
therapy after PCI (guidelines from the ACCF/AHA/SCAI for the
management of PCI recommend continuing therapy with
ASA indefinitely)4
WOEST showed that combining
an OAC (VKA) and clopidogrel
was safe and effective1
Prasugrel and ticagrelor were
permitted at the discretion of
the investigator as they are
recommended in ACS
guidelines2,3
1. Dewilde WJ et al, Lancet 2013;381:1107–1115; 2. Steg PG et al, Eur Heart J 2012;33:2569–2619;
3. Roffi M et al, Eur Heart J 2016;37:267–315; 4. Levine GN et al, Circulation 2011;124:e574–e651

Endpoint Analysis period Analysis set
Primary safety endpoint
Clinically significant bleeding
(major bleeding, minor bleeding or
bleeding requiring medical attention*)
Treatment-emergent period#
(primary)
Post-randomization period
(supportive)
Safety analysis set‡
Secondary endpoints
Components of the primary safety endpoint Treatment-emergent period# Safety analysis set‡
Composite of a major adverse CV event (MI, stroke
or CV death)
Treatment-emergent period# Safety analysis set‡
Components of a major adverse CV event or stent
thrombosis
Treatment-emergent period# Safety analysis set‡
*Bleeding events were classified according to the TIMI scale; #the treatment-emergent period was the time from the first study drug
administration up to 2 days after drug discontinuation; ‡the safety analysis set consisted of all randomized patients who received at
least one dose of study drug
Gibson CM et al, Am Heart J 2015;169:472–478e5
PIONEER AF-PCI
Primary and Secondary Endpoints

Key inclusion
criteria
Key exclusion
criteria
 Medical history of paroxysmal, persistent or permanent NVAF
 Undergone PCI with stent placement for primary atherosclerotic
disease
 INR ≤2.5 at randomization
*Including, but not limited to, platelet count <90,000/µl at screening, history of ICH, 12-month history of clinically significant GI
bleeding, non-VKA-induced elevated PT at screening, anaemia of unknown cause with a haemoglobin level <10 g/dl (<6.21 mmol/l) or
significant liver disease or liver function test abnormalities
Janssen Scientific Affairs, LLC. 2016. https://clinicaltrials.gov/ct2/show/NCT01830543 [accessed 14 Oct 2016]
 Contraindication for anticoagulant or antiplatelet therapy or
unacceptable risk of bleeding*
 History of stroke or TIA
 CrCl <30 ml/min at screening
PIONEER AF-PCI
Key inclusion and exclusion criteria

Remarks
 OAC are needed for preventing stroke.
 Antiplatelet drugs are needed for preventing ST.
 Combining OAC and APT increases bleeding.
 Therefore, there is a need to clarify the optimal
combination regimen in terms of choice of agents,
dose and duration.
 PIONEER AF-PCI is the first RCT to address this
issue with NOACs.
 Given the safety and convenience advantages of
Rivaroxaban over VKA, this is of paramount
importance.
In AF and PCI, these are the facts:

Pacientes con FA que sufren un SCA y son sometidos a intervención coronaria percutánea. Guías y preguntas abiertas

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Pacientes con FA que sufren un SCA y son sometidos a intervención coronaria percutánea. Guías y preguntas abiertas