Anticoagulación en pacientes sometidos a cardioversión y ablación

Merino 1
Novedades en el manejo del paciente con FA; actualización tras el congreso de la AHA
Anticoagulación
en ptes sometidos a
Cardioversión y Ablación
Jose L. Merino
Hospital Universitario La Paz
Madrid, ES

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Conflictos de Interés
● Boehringer: investigador estudios clínicos (RECIRCUIT-
AF)
● Bayer: conferenciante, soporte de investigación,
investigador estudios clínicos (ROCKET-AF)
● Daiichi-Sankyo: advisory board y miembro del exec
steering committee del estudio ENSURE-AF, investigador
estudio ENGAGE-AF y NOAH-AF
● Pfizer: consultoría, investigador estudios clínicos
(AXAFA)
● Sanofi: coordinador nacional estudio BOREALIS-AF

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Cardioversión
Eléctrica

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CVE de FA
● Incidencia de ACV tras la CVE
 Sin anticoagulación: 5-7%
 Con anticoagulación: 0.5%
● ACO en guías clínicas con AVK:
antes (3 sem o ETE) y tras la CVE (4 sem)
● Problemas:
 Frequentes oscilaciones INR  retraso CVE
 CVE no indicación aprobada para NOACs

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CVE de FA
● ACODs:
 Análisis PostHoc de estudios fase III
 Estudios prospectivos
o Rivaroxaban  XVERT
o Edoxaban  ENSURE AF
o Apixaban  EMANATE

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X-VeRT: primary endpoints
Primary efficacy endpoints1 Primary safety endpoint1
A composite of:
• Stroke and TIA
• Non-CNS systemic
embolism
• Myocardial infarction
• Cardiovascular death
• Major bleeding
(ISTH definition)2
1. Cappato R et al. Eur Heart J 2014: doi: 10.1093/eurheartj/ehu367;
2. Schulman S et al. J Thromb Haemost 2005;3:692–694
All endpoints adjudicated by treatment assignment-blinded
Clinical Endpoint Committee

X-VeRT: study population
mITT population
(primary analysis set)
All ITT patients without LA/LAA thrombi
Randomized
(N=1504)
ITT population
All patients randomized
Rivaroxaban
(n=1002)
Rivaroxaban
(n=978)
VKA
(n=502)
VKA
(n=492)
Rivaroxaban
(n=988)
VKA
(n=499)
Safety population
Patients receiving
≥1 dose of study drug
Screening
(N=1584) Excluded (n=80)
• Screening failure (n=71)
• Withdrawal by patient (n=7)
• Adverse event (n=2)
34 patients (24 rivaroxaban, 10 VKA) were not included in the mITT population
(n=1470; 978 rivaroxaban, 492 VKA) due to the identification of an LA thrombus
Cappato R et al. Eur Heart J 2014: doi: 10.1093/eurheartj/ehu367;
Cappato R. ESC Congress 2014. Oral presentation 4945
2:1

30-day follow-
up
OAC
Design: randomized, open-label, parallel-group, active-
controlled multicentre study
Early
Delayed
Cardioversion
strategy
1–5 daysR
Rivaroxaban 20
mg od*
VKA
2:1
2:1
≥21 days
(max. 56 days)
Rivaroxaban 20
mg od*
VKA
R
Inclusion criteria:
Age ≥18 years, non-valvular AF lasting >48 h or
unknown duration, scheduled for cardioversion
Ezekowitz MD et al. Am Heart J 2014;167:646–652; www.clinicaltrials.gov. NCT01674647
42 days
42 days
Rivaroxaban 20
mg od*
VKA
Rivaroxaban 20
mg od*
VKA
Endofstudytreatment
CardioversionCardioversion

X-VeRT: primary efficacy endpoints
Rivaroxaban
(N=978)
VKA
(N=492)
Risk ratio
(95% CI)
% n* % n*
Primary efficacy endpoint 0.51 5 1.02 5 0.50 (0.15–1.73)
Stroke 0.20 2 0.41 2
Haemorrhagic stroke 0.20 2 0
Ischaemic stroke 0 0.41 2
TIA 0 0
Non-CNS SE 0 0.20 1
MI 0.10 1 0.20 1
Cardiovascular death 0.41 4 0.41 2
*Number of patients with events; patients may have experienced more than one primary efficacy event
mITT population
Cappato R et al. Eur Heart J 2014: doi: 10.1093/eurheartj/ehu367

X-VeRT: time to cardioversion by cardioversion strategy
*Reason for not performing cardioversion as first scheduled from 21–25 days primarily due to inadequate anticoagulation
(indicated by drug compliance <80% for rivaroxaban or weekly INRs outside the range of 2.0–3.0 for 3 consecutive weeks
before cardioversion for VKA)
Patients(%)
Delayed cardioversion
77,0
36,3
0
20
40
60
80
100 Rivaroxaban VKA
p<0.001
1 patient with
inadequate
anticoagulation
95 patients with
inadequate
anticoagulation
Cappato R et al. Eur Heart J 2014: doi: 10.1093/eurheartj/ehu367
Median time to cardioversion
Days
0
20
40
60
80
100
Early Delayed
p=0.628
p<0.001
Rivaroxaban
VKA
22 days
30 days
Patients cardioverted as scheduled*

Patients Undergoing Catheter
Ablation or CV in XANTUS
Camm AJ et al. Eur Heart J 2016;37:1145–1153
Camm AJ et al. AHA 2016

Outcomes after Intervention across
Four Prospective Rivaroxaban Studies
Camm AJ et al. AHA 2016

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ENSURE-AF
●Pacientes FA ≥48 hs y ≤12 meses
●Objetivo primario: Edoxaban vs mejor tratamiento
posible (warfarina±enoxaparina) para CVE de FA no
valvular
●Aleatorización: 1:1 en varios estratos
●Estratificación:
 ACO convencional de 3 semanas o guiada por ETE
(decidido por investigador local)
 Nuevo o ya tratado con ACO
 Dosis de Edoxaban (60 mg o corregida a 30 mg al dia) B

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Overall Study Design
Lip GY, et al. Am Heart J. 2015;169:597-604
Duration of follow-up = 28 + 30 days
Enoxaparinb +
Warfarin (INR, 2.0–3.0)
Early cardioversion
(TEE-guided stratum)
Delayed cardioversion
(non-TEE-guided stratum)
RANDOMIZATION
1:1 randomization into 2 anticoagulation treatment groups per stratum
Patients with documented NVAF planned for cardioversion
Edoxaban
(60/30 mg once daily)a
Edoxaban
(60/30 mg once daily)b
Enoxaparinb +
Warfarin (INR, 2.0–3.0)
B

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Non-TEE-guided Stratum
Pre-Treatment
(Day –14)
CVN
(Day 0)
Post-CVN
Treatment
28 Days
End of Treatment
(Day 28)
Follow-Up Period
30 Days
Discontinuation/
Follow-Up Visit
(Day 58)
Warfarin Arm
Edoxaban Arm
Randomization
Baseline/
Randomization
(Day –21)
Pre-Treatment
(Day –7)CVN = cardioversion; TEE = transesophageal echocardiography
B

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TEE-guided Stratum
Baseline/
Randomization
(Day –3)
TEE/CVN
(Day 0)
Post-CVN
Treatment
28 Days
End of Treatment
(Day 28)
Follow-Up Period
30 Days
Discontinuation/
Follow-Up Visit
(Day 58)
Warfarin Arm
Edoxaban Arm
CVN = cardioversion; TEE = transesophageal echocardiography
Randomization
B

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Endpoints
CRNM = clinically relevant nonmajor; CV = cardiovascular; ITT = intent-to-treat; MI = myocardial infarction; SEE = systemic embolic event
Composite of stroke, SEE, MI, and CV mortality
ITT population (all randomized subjects) during the overall period
Primary Efficacy Endpoint
Composite of major and CRNM bleeding
Safety population (all subjects who took ≥1 dose of study drug) during the on-treatment period
Primary Safety Endpoint
Composite of stroke, SEE, MI, CV mortality, and major bleeding
ITT population (all randomized subjects) during the overall period
Net Clinical Outcome (Secondary Endpoint)
B

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Patient Disposition
N = 2199
Edoxaban
(n = 1095)
Yes: 1067 (97.4%)
No: 28 (2.6%)
988 (90.2%)
Cardioversion Performed
or Auto-converted:
Received Study Drug:
Randomized (1:1):
1041 (95.1%)
1001 (91.4%)
0 (0%)
Enoxaparin + Warfarin
(n = 1104)
Yes: 1082 (98.0%)
No: 22 (2.0%)
966 (87.5%)
Completed Study:
Completed Treatment:
Lost to Follow-up:
Median time
to cardioversion:
TEE stratum = 2.0 d
Non-TEE stratum = 23 d
Median time
to cardioversion:
TEE stratum = 2.0 d
Non-TEE stratum = 23 d
1041 (95.1%)
1001 (91.4%)
1 (0.1%)
B

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Primary Efficacy
0,0
0,5
1,0
1,5
2,0
Total by Treatment TEE Stratum Non-TEE Stratum
CompositeofStroke,SEE,
MI,andCVDeath,%
Edoxaban
Enoxaparin + Warfarin (mean TTR = 70.8%)
5/1095 11/1104
0.5%
1.0%
0.3%
0.8%
0.6%
1.2%
OR (95% CI):
0.46 (0.12–1.43)
OR (95% CI):
0.40 (0.04–2.47)
OR (95% CI):
0.50 (0.08–2.36)
2/589 5/599 3/506 6/510
B

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Fichas técnicas
Rivaroxaban

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Fichas técnicas
Rivaroxaban

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Fichas técnicas
Dabigatran
Apixaban
Edoxaban
Nada

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Abl de FA
● Riesgo de eventos embólicos (hasta 1%) pero también
hemorrágico (3%)

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Abl con/sin AvK
Di biase et al . Circulation 2010
No AvK
8 mm
No AvK
Irrigado
AvK
Irrigado

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Abl de FA
● Riesgo de eventos embólicos y hemorrágicos
● ACO con AVK para peri Abl en guías clínicas con AVK:
 Mantenerla durante el procedimiento
 Al menos 8 semanas tras el mismo
● Muchos pacientes ya siguen tratamiento con ACODs y
no es práctico su paso a AVK
● ¿Es seguro mantener ACOD?
¿ACV/Hemorragia?¿Resolucion de taponamientos?

VENTURE AF: Participating Countries
 248 patients randomized from 37 centres across 5 countries
 Patients were screened between February 2013 and September 2014
Germany
France
UK
South Africa
Belgium
USA
Cappato R et al. Eur Heart J 2015

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VENTURE AF: Study Treatment
●Comparison:
Uninterrupted rivaroxaban 20 mg once
daily
Uninterrupted dose-adjusted VKA to
achieve a target INR of 2.0–3.0
●During ablation, patients received
intravenous unfractionated heparin (ACT
of 300–400 sec)
Naccarelli GV et al, J Interv Card Electrophysiol 2014;41:107–116

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VENTURE AF:
Key Inclusion and Exclusion Criteria
Key inclusion criteria
 Scheduled for catheter ablation
for NVAF
 Prior paroxysmal (<1 week) or
persistent (>1 week and <1 year
or requiring pharmacological or
electrical cardioversion) or
long-standing persistent (≥1
year) NVAF
 Suitable for anticoagulant
therapy and catheter ablation
Key exclusion criteria
 Prior stroke, TIA or non-
convulsive status epilepticus ≤6
months
 Prior major bleeding or a
thromboembolic event ≤12
months
 Major surgery ≤6 months
before screening/planned
during study
 MI ≤2 months or CABG surgery
≤6 months
 Non-cardiac or reversible
NVAF
 CrCl ≤50 ml/min‡

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VENTURE AF Design:
Randomized, Open-label, Active-controlled Multicentre
1–7 days 30±5 days
Rivaroxaban 20 mg
od
N=24
8
Planned TEE
or ICE
Sufficient
anticoagulatio
n
Insufficient
anticoagulatio
n
1:1
1:1
Catheter
ablation
R
124
Catheter
ablation
Rivaroxaban 20 mg od
VKA (INR 2.0–3.0)
VKA (INR 2.0–3.0)
Rivaroxaban 20 mg
od
VKA (INR 2.0–3.0)
End of
treatment
Rivaroxaban 20 mg od
VKA (INR 2.0–3.0)
4–5 weeks 30±5 days
R
124
Patients with Px, Ps
or long-standing Ps
NVAF
Naccarelli GV et al, J Interv Card Electrophysiol 2014;41:107–116
Heparin iv ACT 300–400 sec
(target 300–325 sec)

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VENTURE AF: Patient Flow
No patients were lost to follow-
upCappato R et al. Eur Heart J 2015
Screened (n=291)
Randomized (n=248)
Rivaroxaban (n=124) VKA (n=124)
ITT population
All patients who met inclusion and
exclusion criteria and were
randomized
Safety population (n=244)
All patients who also received
≥1 dose of study drug
Per-protocol population
(n=221)
All patients who also underwent
catheter ablation
43 patients
• Screening failure (n=43)
3 patients
• Withdrawal of consent
(n=1)
• Physician decision (n=1)
• Other (n=1)
1 patient
• Other (n=1)
14 patients
• Withdrawal of consent
(n=2)
• Physician decision (n=1)
• Non-compliance with
study drug (n=1)
• Other (n=6)
9 patients
• Protocol violation
(n=1)
• Other (n=3)

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VENTURE AF:
Serious Adverse Events Leading to…
…drug discontinuation …hospitalization
2.5
0.8
0
2
4
6
8
10
SAEsleadingtodiscontinuation(%)
VKA
Rivaroxaban
14.0
8.9
0
2
4
6
8
10
12
14
16
VKA
Rivaroxaban
SAEsleadingtohospitalization(%)

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VENTURE AF: Clinical Implications:
Rivaroxaban in the Ablation Setting
Results of VENTURE AF consistent
with real-life studies…
… and ROCKET AF
cardioversion/ablation
subanalysis
1,9
5.0
0,3
1,6
5
0,3
0
2
4
6
8
10
Major
bleeding
Minor
bleeding
Thrombo-
embolism
Proportionofpatients(%)
Warfarin
Rivaroxaban
3 4
48
21
3 2
50
30
0
10
20
30
40
50
60
Stroke/SE CV death Hospitalization MB
or NMCRB
Warfarin
Rivaroxaban
Numberofevents
Outcomes after cardioversion and ablation*
(n=321)2
North American registry
(n=642)1
*The analysis combined patients undergoing ablation (n=79) with patients undergoing cardioversion (n=285)
1. Lakkireddy D et al. J Am Coll Cardiol 2014;63:982–988
2. Piccini J et al. J Am Coll Cardiol 2013;61:1998–2006

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Otros estudios
●EMANATE: CVE Apixaban
●RECIRCUIT-AF: ABL Dabigatran
●AXAFA: ABL Apixaban
●ELIMINATE: ABL Edoxaban

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Conclusiones
Cardioversión
● Existen suficientes evidencias para plantear la CVE con continuacion o inicio
de ACODs, especialmente con Rivaroxaban y Edoxaban
● El uso de ACODs presenta claras ventajas como el evitar el retraso del
procedimiento o un manejo mas sencillo
Ablación
● Mantener la anticoagulación durante la ablacion y 8 semanas tras esta ha
demostrado una reducción de complicaciones
● Estudios no controlados y controlados con Rivaroxaban no han encontrado
diferencias significativas con los AVK
● Hay estudios en marcha para validar este hallazgo con otros ACODs
● Actualmente se recoge en la guías clínicas la validez de los ACODs para esta
indicación

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Gracias!!
jlmerino@arritmias.net

Anticoagulación en pacientes sometidos a cardioversión y ablación

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