Fundación EPIC _ Left atrial appendage closure. Clinical evidence; where we are? By Raul Moreno

Left atrial appendage
closure. Clinical
evidence: where we are?
Raúl Moreno
Hospital La Paz, Madrid, SP

2015 2016 2017
640
496
334
Utilización del cierre de orejuela en España
≈ 3.000 ablaciones de
FA en España al año.
Datos SHCI
Bradley BC, et al. Am J Cardiol. 2000;85:568–572.

2015 2016 2017
640
496
334
• > 1 millón de pacientes con FA en España.
• ≈ 1 de cada 2.000 FA se trata con cierre de orejuela.
Datos SHCI

2015 2016 2017
640
496
334
Datos SHCI
• > 20% tienen alguna contraindicación para ACO.
• > 20% interrumpen el tratamiento anticoagulante.
• < 1/800 con problemas para anticoagulación se
tratan con cierre de orejuela.

2015 2016 2017
640
496
334
Datos SHCI
• > 20% tienen alguna contraindicación para ACO.
• > 20% interrumpen el tratamiento anticoagulante.
• < 1/800 con problemas para anticoagulación se
tratan con cierre de orejuela.
¿Por qué se utiliza tan poco?
¿Es que no tenemos evidencia?

Opinión personal…
• El cierre de orejuela tiene un futuro tremendo.
• Los resultados del procedimiento han mejorado progresivamente y
en la actualidad la seguridad no es un problema serio.
• Pero desde que existe esta terapia, no se ha construido la evidencia
suficiente.
• Los estudios aleatorizados en pacientes candidatos a
anticoagulación no han mostrado el beneficio esperado, y se han
comparado con antagonistas de la vitamina K.
• En los próximos años, tendremos muchos estudios aleatorizados
que seguro servirán para generalizar esta terapia.
• Mientras tanto, a los que creemos en sus beneficios, nos costará
convencer de la generalización del procedimiento.

Recommendation Class Level
LAA occlusion may be considered for stroke
prevention in patients with AF and contra-
indications for long-term anticoagulant
treatment (e.g. those with a previous life-
threatening bleed without a reversible cause).
IIb B
Eur Heart J 2016;37:2893–2962.
ESC/EHRA/ESO guidelines
• PREVAIL trial (J Am Coll Cardiol 2014;64:1–12).
• PROTECT AF (JAMA 2014;312:1988–1998.).
• PREVAIL & PROTECT meta-analysis (JACC 2015;65:2614-23.)
• ASAP (J Am Coll Cardiol 2013;61:2551 – 2556.)

IIb or not IIb, that is the
question
Recommendation Class Level
LAA occlusion may be considered for stroke
prevention in patients with AF and contra-
indications for long-term anticoagulant
treatment (e.g. those with a previous life-
threatening bleed without a reversible cause).
IIb B
Eur Heart J 2016;37:2893–2962.
ESC/EHRA/ESO guidelines
• PREVAIL trial (J Am Coll Cardiol 2014;64:1–12).
• PROTECT AF (JAMA 2014;312:1988–1998.).
• PREVAIL & PROTECT meta-analysis (JACC 2015;65:2614-23.)
• ASAP (J Am Coll Cardiol 2013;61:2551 – 2556.)

Recommendation Definition Suggested wording of use
Class I
Evidence and/or general
agreement that it is beneficial,
useful, and effective
Indicated
Class II
Conflicting evidence and/or a
divergence of opinion about the
usefulness/efficacy
Class IIa In favor of usefulness/efficacy. Should be considered
Class IIb
Less well established by
evidence/opinion
May be considered
Class III
Evidence and/or general
agreement that it is not useful/
effective and in some cases may
be harmful
Not indicated
LEVELS OF RECOMMENDATION

POINT/COUNTERPOINT
Percutaneous left atrial appendage closure is not ready
for routine clinical use
John Mandrola, MD,* Andrew Foy, MD,†
Gerald Naccarelli, MD, FHRS†
From the *Baptist Health Louisville, Louisville, Kentucky, and †
Penn State University College of Medicine,
Hershey, Pennsylvania.
In this review, we challenge the use of left atrial appendage
(LAA) occlusion with Watchman for stroke prevention in
patients with atrial fibrillation on the basis of 1) unreliable
and divergent results of the regulatory trials; 2) a strong infe-
riority signal from the Prospective Randomized Evaluation
of the Watchman LAA Closure Device In Patients With
Atrial Fibrillation Versus Long Term Warfarin Therapy
(PREVAIL) trial; 3) an uncertain pathophysiological basis
for LAA occlusion; and 4) insufficient data to support
Watchman in patients ineligible for anticoagulation.
Watchman vs non–vitamin-K-antagonist
anticoagulant trials
Both Watchman and non–vitamin-K-antagonist anticoagu-
tection in Patients With Atrial Fibrillation (PROTECT-AF)
and PREVAIL trials assigned 463 and 269 patients to the
experimental arms and 244 and 138 patients to the control
arms, respectively.5,6
Watchman investigators were able to use smaller numbers
of patients because of their choice of Bayesian vs traditional
frequentist trial design. Instead of powering a trial to detect
a prespecified difference of X%, Bayesian methods model
the probability of a treatment effect based on the results of pre-
vious trials and update this probability as events accumulate.
If accumulating data support and increase the probability of
futility or success, investigators may reach a conclusion faster
and with a smaller number of patients and events. Traditional
frequentist designs may require larger numbers because they
do not account for prior probability at any point in a trial and
Mandrola J, et al. Heart Rhythm. 2018 Feb;15(2):298-301.
Not all are believers as do we

Evidencia en cierre de orejuela
• ¿Qué nos gustaría tener?
• ¿Qué tenemos?
• ¿Qué podremos tener en el futuro?
¿Qué población “queremos”?
• ¿Sólo con ACO/NACO contraindicada?
• ¿Alto riesgo hemorrágico?
• ¿En sustitución a ACO/NACO?
¿Qué le pedimos al cierre de orejuela?
• ¿Es suﬁciente reducción de hemorragias?
• ¿También reducción de ictus?
Ictus hemorrágico vs isquémico

• AF with CHADS2 ≥ 1, without contraindications to warfarin (n=707).
• Enrolled from 02/2005 to 06/2008 (ended 10 years ago!!!).
• LAAC (Watchman) vs warfarin (2:1).
• Antithrombotic treatment after LAAC:
• 45 days: warfarin (INR 2-3).
• Warfarin discontinuation if 45-day TEE showed either complete
closure or residual peri-device flow (jet <5 mm).
• 45 days - 6 mo: clopidogrel (75 mg) & aspirin (81–325 mg).
• > 6 mo: aspirin alone indefinitely.
• Primary end-point: (non-inferiority design)
• Efficacy: stroke (ischaemic or haemorrhagic), cardiovascular or
unexplained death, or systemic embolism.
• Safety: bleeding (eg, intracranial or gastrointestinal bleeding) or
procedure-related complications (eg, serious pericardial effusion,
device embolisation, procedure-related stroke).
Randomized PROTECT-AF trial
Holmes DR, et al Lancet 2009; 374: 534–42

PROTECT-AF
Efﬁcacy Stroke CV death* Embolism Safety*
4,4
0
2,7
3,2
4,9
7,4
0,3
0,7
2,3
3
LAAC
Warfarin
*p<0.05
Mean FU: 18±10 mo.

PROTECT-AF
Efﬁcacy Stroke CV death* Embolism Safety*
4,4
0
2,7
3,2
4,9
7,4
0,3
0,7
2,3
3
LAAC
Warfarin
Ischemic Hemorrhagic*
1,61,6
0,1
2,2 *p<0.05
Mean FU: 18±10 mo.

PROTECT-AF
• Efficacy: non-inferiority vs warfarin.
• Significant reduction (>90%) in hemorrhagic stroke.
• No stroke reduction.
• Safety.
an implant was attempted,
roll-in patients, serious
11/154) of the first three
% (17/388) of subsequent
olisation occurred in three
g the procedure and two
n day 45. One device
rcutaneously by use of a
wo patients underwent
concomitant aortic valve
ation was not associated
Intervention
(n=463)
Control
(n=244)
Serious pericardial effusion* 22 (4·8%) 0
Major bleeding† 16 (3·5%) 10 (4·1%)
Procedure-related ischaemic stroke 5 (1·1%) 0
Device embolisation 3 (0·6%) 0
Haemorrhagic stroke‡ 1 (0·2%) 6 (2·5%)
Other§ 2 (0·4%) 0
*Defined as the need for percutaneous or surgical drainage. †Major bleeding is
defined as a bleeding event that required at least 2 units of packed red blood cells

Longer FU make benefit more evident: PROTECT-AF long-term
Reddy VY et al. JAMA. 2014;312:1988-98.
interpretation of event rates, but truncated exposure pre-
venting detection or registration of events would be more
tively) found the device strateg
the primary efficacy end point.
cardiovascular/unexplained death.
c
Disabling or fatal strokes were those with a Modified Rankin Score of 3-6 after
ventionorprolongedhospitalization,proc
zation)andmajorbleeding(intracranialor
Figure 2. Kaplan-Meier Curves for the Primary Efficacy and Safety End Points
30
20
10
0
No. of patients
Device
Device
Device
Warfarin
Warfarin
0
463
244
6
398
230
6
376
228
18
370
210
18
357
207
30
345
188
30
341
183
48
317
147
42
327
159
42
320
153
12
382
218
24
360
200
36
337
173
54
285
121
54
277
117
60
196
87
PatientsWithEvents,%
Time Since Randomization, d
Primary efficacy end pointA
30
20
10
0
0
463
244
12
364
214
24
353
195
36
332
169
48
310
139
60
190
86
PatientsWithEvents,%
Time Since Randomization, d
Primary safety end pointB
HR (95% CI), 0.61 (0.38-0.97)
P =.04
HR (95% CI), 1.21 (0.78-1.94)
P =.41
Warfarin

e, Cardiovascular Mortality, and All-Cause Mortality
Device
DeviceWarfarin
Warfarin
0
56
64
25
20
15
10
5
0
0
463
244
12
389
222
24
372
204
36
351
176
48
328
147
60
165
69
CardiovascularMortality,%
Time, mo
Cardiovascular mortalityB
25
20
15
10
5
0
0
463
244
12
389
222
24
373
204
36
352
177
48
330
150
60
202
92
All-CauseMortality,%
Time, mo
All-cause mortalityC
HR (95% CI), 0.40 (0.21-0.75)
P =.005
HR (95% CI), 0.66 (0.45-0.98)
P =.04
Left Atrial Appendage Closure vs Warfarin for Atrial Fibrillation
PROTECT-AF long-term

Table 2. Intention-to-Treat Primary Efficacy and Safety Outcomes According to Treatment Group by Bayesian Model
Event
Device Group (n = 463) Warfarin Group (n = 244)
Device/Warfarin
Rate Ratio (95%
Credible Interval)
Events/Patient-
Years
Observed
Ratea
Events/Patient-
Years
Observed
Ratea
Primary efficacy end
pointb
39/1720.2 2.3 (1.7-3.2) 34/900.8 3.8 (2.5-4.9) 0.60 (0.41-1.05)
Stroke 26/1720.7 1.5 (1.0-2.2) 20/900.9 2.2 (1.3-3.1) 0.68 (0.42-1.37)
Ischemic 24/1720.8 1.4 (0.9-2.1) 10/904.2 1.1 (0.5-1.7) 1.26 (0.72-3.28)
Hemorrhagic 3/1774.2 0.2 (0.0-0.4) 10/916.2 1.1 (0.5-1.8) 0.15 (0.03-0.49)
Disablingc
8/1771.3 0.5 (0.2-0.8) 11/912.7 1.2 (0.6-1.9) 0.37 (0.15-1.00)
Nondisablingc
18/1723.7 1.0 (0.7-1.7) 9/907.7 1.0 (0.4-1.7) 1.05 (0.54-2.80)
Systemic
embolization
3/1773.6 0.2 (0.0-0.4) 0/919.5 0 NA
Cardiovascular or
unexplained death
17/1774.3 1.0 (0.6-1.5) 22/919.4 2.4 (1.4-3.4) 0.40 (0.23-0.82)
Primary safety end
pointd
60/1666.2 3.6 (2.8-4.6) 27/878.2 3.1 (2.0-4.3) 1.17 (0.78-1.95)
Abbreviation: NA, not applicable.
a
Events per 100 patient-years (95% credible interval).
b
Primary efficacy defined as composite of stroke, systemic embolization, or
cardiovascular/unexplained death.
the stroke. Nondisabling strokes were those
0-2 after the stroke.
d
Safetydefinedasprocedure-relatedevents(p
ventionorprolongedhospitalization,procedu
zation)andmajorbleeding(intracranialorblee
Left Atrial Appendage Closure vs Warfarin for Atrial Fibrillation
PROTECT-AF long-term

Holmes et al. J Am Coll Cardiol 2014;64:1–12
• AF with CHADS2 ≥ 2, without contraindications to warfarin (n=407).
• LAAC (Watchman) vs warfarin (2:1).
• Antithrombotic treatment after LAAC: as in PROTECT-AF.
• End-points:
• Primary efficacy: stroke (ischaemic or haemorrhagic), cardiovascular
or unexplained death, or systemic embolism.
• Late efficacy: ischemic stroke or systemic embolism, excluding the
first 7 days after randomization.
• Early safety: all-cause death, ischemic stroke, SE, or device-/
procedure-related events requiring open cardiovascular surgery or
major endovascular intervention such as surgical treatment of a
pseudoaneurysm between randomization and within 7 days of the
procedure or during the index hospitalization (nonsurgical treatment of
complications not included).
Randomized PREVAIL study

Holmes et al. J Am Coll Cardiol 2014;64:1–12
Efficacy Late efficacy
2
6,3
2,5
6,4
LAAC
Warfarin
Non-inferiority
not met
Non-inferiority
met
creased from 1.6% to 0.4% (p ¼ 0.027); effusions
quiring pericardiocentesis or a pericardial window
re numerically lower in PREVAIL (1.5% [4 of 265]
PROTECT AF 2.9% [13 of 449]; p ¼ 0.36), although
e absolute number of events was small. Procedural
d device-related strokes decreased, from 1.1% in
OTECT AF to 0.4% in PREVAIL (p ¼ 0.007). Device
mbolization was infrequent, occurring in only 4 pa-
nts (2 in PROTECT AF, 2 in PREVAIL) and was not
tistically significantly different across the studies
ble 7).
An important component of this analysis was
aluation of the learning curve with new versus
perienced operator sites. Implantation success was
hieved in 95.1% overall and in 96.3% with experi-
ced operators versus 93.2% with new operators
was noninferior to warfarin for the occurrence of
late ischemic events, such as ischemic stroke or SE
TABLE 5 Safety Coprimary Endpoint Results and Events by Type
(Intention-to-Treat): Device Group Only
% (n/N) 95% CrI
Safety primary endpoint results 2.2% (6/269) 2.652%
No. of Events % of Subjects
Safety events by type
Device embolization 2 0.7
Arteriovenous fistula 1 0.4
Cardiac perforation 1 0.4
Pericardial effusion with cardiac tamponade 1 0.4
Major bleed requiring transfusion 1 0.4
Abbreviation as in Table 2.
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secondary to LAA thrombus. This pathophysiology
led to the widespread application of anticoagulant
therapy, initially with warfarin, which has been
proven superior to aspirin for stroke prevention (22).
Multiple problems with warfarin, however, have been
identified, including bleeding, contraindications to
its application, patient compliance, and the need for
routine monitoring (23–26). Thus, it is estimated that
anticoagulation is not currently used in up to 50% of
eligible AF patients, which led to the development of
new oral anticoagulants (NOACs), whose efficacy
have been established in randomized clinical trials
(7–9). The rates of bleeding with approved doses of
TABLE 7 Comparison of Outcomes in Device Patients in PROTECT AF,
CAP, and PREVAIL
PROTECT AF CAP PREVAIL p Value
Implant success 90.9 94.3 95.1 0.04
All 7-day procedural complications 8.7 4.2 4.5 0.004
Pericardial effusion requiring surgery 1.6 0.2 0.4 0.03
Pericardial effusion with pericardiocentesis 2.4 1.2 1.5 0.318
Procedure-related strokes 1.1 0.0 0.7 0.02
Device embolization 0.4 0.2 0.7 0.368
Abbreviations as in Tables 3 and 6.
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18 mo. rates

Efﬁcacy Late efﬁcacy
1,4
5,1
2,6
6,6
LAAC
Warfarin
5-yr follow-up
Non-inferiority
not met
Non-inferiority
met
TCT 2017

Reddy VY, et al. J Am Coll Cardiol 2017;70:2964–75
5-year data from PROTECT-AF and PREVAIL
score and modified HAS-BLED score (Figure 2).
A consistent treatment effect was also observed in
patients with prior stroke or transient ischemic
attack—patients who enrolled in the trials for
LAAC (HR: 0.73; 95% CI: 0.54 to 0.98; p ¼ 0.035).
The Kaplan-Meier estimate of all-cause death is
shown in Figure 1. For major bleeding, including
those bleeds occurring at the time of the procedure
TABLE 4 5-Year Patient-Level Meta-Analysis of PROTECT AF and PREVAIL (2:1 Randomization)
Device Group
(n ¼ 732)
Control Group
(n ¼ 382)
Hazard Ratio
(95% Confidence Interval) p ValueNo. of Events
Rate
(per 100 PY) No. of Events
Rate
(per 100 PY)
Efficacy: stroke/SE/CV death 79/2,856.0 2.8% 50/1,472.8 3.4% 0.82 (0.58–1.17) 0.27
All stroke or SE 49/2,849.4 1.7% 27/1,472.9 1.8% 0.96 (0.60–1.54) 0.87
Ischemic stroke or SE 45/2,850.2 1.6% 14/1,479.1 0.95% 1.71 (0.94–3.11) 0.08
Hemorrhagic stroke 5/2,954.8 0.17% 13/1,499.0 0.87% 0.20 (0.07–0.56) 0.0022
Ischemic stroke or SE >7 days 37/2,862.1 1.3% 14/1,479.1 0.95% 1.40 (0.76–2.59) 0.28
Disabling stroke 13/2,943.0 0.44% 15/1,493.8 1.0% 0.45 (0.21–0.94) 0.03
Nondisabling stroke 31/2,879.1 1.1% 12/1,484.3 0.81% 1.38 (0.71–2.68) 0.35
CV/unexplained death 39/2,960.5 1.3% 33/1,505.2 2.2% 0.59 (0.37–0.94) 0.027
All-cause death 106/2,961.6 3.6% 73/1,505.2 4.9% 0.73 (0.54–0.98) 0.035
Major bleeding, all 85/2,748.4 3.1% 50/1,414.7 3.5% 0.91 (0.64–1.29) 0.60
Major bleeding, non-procedure-related 48/2,853.6 1.7% 51/1,411.3 3.6% 0.48 (0.32–0.71) 0.0003
Two strokes in PREVAIL are excluded because the baseline MRS score was unavailable. Disabling stroke is defined as a stroke that increases the Modified Rankin Score by $2.
PY ¼ patient-yrs. Other abbreviations as in Table 3.

Reddy VY, et al. J Am Coll Cardiol 2017;70:2964–75
5-year data from PROTECT-AF and PREVAILTRAL ILLUSTRATION Stroke Prevention in Nonvalvular Atrial Fibrillation With LAA Closure
0.01
10
0.1 1 10
MHazard Ratio (95% CI)
Efficacy
HR p-value
All-cause death
Major bleed, all
Major bleeding, non procedure-related
All stroke or SE
Ischemic stroke or SE
Hemorrhagic stroke
Ischemic stroke or SE >7 days
Disabling/Fatal Stroke (MRS change of ≥2)
Non-Disabling Stroke
CV/unexplained death
0.82
0.73
0.91
0.48
0.96
1.7
0.2
1.4
0.45
1.37
0.59
0.3
0.04
0.6
0.0003
0.9
0.08
0.0022
0.3
0.03
0.35
0.03
Favors WarfarinFavors WATCHMAN

gastrointestinal
closure is asso
hazard, there i
between bleedin
implantation (e
matoma) and no
bleeding: the f
where medical c
the latter may o
accessible.
The reducti
compared with
consistent amo
Paradoxically, w
LAA closure in p
possibly becaus
bleeding in pati
Patients with h
TABLE 4 Types and Frequencies of Major Bleeding Events That
Occurred After the Period of Adjunctive Pharmacotherapy (OAC
and DAPT) in the Device Group (>6 Months Post-Randomization)
LAA Closure
(n ¼ 732)
Warfarin
(n ¼ 382) p Value
Gastrointestinal bleeding 10 (1.4) 21 (5.5) <0.001
Epistaxis 1 (0.1) 1 (0.3) 1.0
Hematuria 0 (0) 2 (0.5) 0.12
Hemorrhagic stroke 2 (0.3) 7 (1.8) 0.01
Cranial bleed 3 (0.4) 1 (0.3) 1.0
Anemia requiring transfusion 2 (0.3) 1 (0.3) 1.0
Major bleed requiring transfusion 1 (0.1) 1 (0.3) 1.0
Other bleeding 0 (0) 1 (0.3) 0.35
Values are n (%). Note that patients were randomly assigned to LAA closure or
warfarin therapy in a 2:1 fashion.
DAPT ¼ dual antiplatelet therapy; LAA ¼ left atrial appendage; OAC ¼ oral
anticoagulation.
D E C E M B E R 2 8 , 2 0 1 5 : 1 9 2 5 – 3 2
Price MJ, et al J Am Coll Cardiol Intv 2015;8:1925–32
1,114 patients were included, with a median follow-up of 3.1 years.
Bleeding complications. PROTECT-AF and PREVAIL studies.

What is the value of registries in a so prevalent disease as AF???
PROTECT- AF CAP PREVAIL ASAP CAP 2 EWOLUTION post-FDA
2,83,84,14,1
7,4
95,6
98,596,094,795,194,4
90,9
Success (%) Safety events 7d (%)
(n=449)
(n=566)
(n=265) (n=579) (n=1,019) (n=3,822)(n=150)

l success and safety of LAAC. Left panel: Evolution of technical success rates (green dots) and periprocedural safety events (orange bars) for the m
e Watchman device. Right panel: Success rates and periprocedural complications are shown for the major trials with the Amplatzer device.
S. Gloekler et al. / International Journal of Cardiology 249 (2017) 234–246
Gloekler S, et al. Int J Cardiol 2017;249:234–246.
What is the value of registries in a so prevalent disease as AF???

Holmes DR, et al. TCT 2017.
CAP registry
• n=566, enrolled from 2008 to 2010 (Watchman).
• 5-yr follow-up.
• Same anti-thrombotic regimen than RCT.
• Higher risk than PROTECT-AF (mean CHADS2 2.5 vs 2.2)Results in Context:
Primary Efficacy Consistent Across Trials
Primary efficacy
Primary efﬁcacy end-point

Boersma LVA, et al. Eur Heart J 2016;37:2465–2474.
EWOLUTION registry
• n=1,021, enrolled from 2013 to 2015 (Watchman).
• Included patients unsuitable for anticoagulation.
• 30-day follow-up (focused on peri-procedural results).
• Only 27% anticoagulation after device implantation.
• Higher risk (mean CHADS2 2.8 vs 2.5 CAP and 2.2 PROTECT-AF)
Figure 1 Implant success in EWOLUTION when compared
with prior WATCHMAN studies.
Figure 2 Serious procedure-/device-related events th
2468 L.V.A. Boers
Figure 1 Implant success in EWOLUTION when compared
with prior WATCHMAN studies.
Figure 2 Serious procedure-/device-related events through
7 days in EWOLUTION when compared with prior WATCH-
MAN studies.
2468 L.V.A. Boersma et al.
Implant success 7-day events

treated with life-long clopidogrel sustained fewer ischemic
strokes that those treated with aspirin alone (relative risk:
0.68; 95% confidence interval: 0.57 to 0.80) (13,15).
Accordingly, if one discounts the expected stroke rate of this
Table 4 Clinical Outcomes
Entire Cohort
Events/Patient-Years*
Primary efficacy 8/175.0 (4.6%)
Death, all cause 9/180.0 (5.0%)
All stroke 4/176.0 (2.3%)
Ischemic stroke 3/176.9 (1.7%)
Hemorrhagic stroke 1/179.1 (0.6%)
The primary efficacy endpoint was defined as the combined events of ischemic stroke, hemorrhagic
stroke, systemic embolism, and cardiovascular/unexplained death. *Events per 100 patient-years.
Reddy VK, et al. J Am Coll Cardiol 2013;61:2551–6
ASAP registry
• n=150, enrolled from 2009 to 2011 (Watchman).
• Ineligible for warfarin (93% history of bleeding).
• No anticoagulation but DAPT after implantation.
• Mean CHADS2 2.8.

Tzikas A. et al. EuroIntervention 2016;11:1170-1179.
6
5
4
3
2
1
0
%
Effectiveness in stroke
reduction vs. estimated
Effectiveness in bleeding
Estimated based on
CHA2
DS2
-VASc score
Observed rate
in study
6
5
4
3
2
1
0
%
Estima
HAS-B
Observ
in stud–59%
5.62%
2.30%
Total
patient-years
Total
patients
Total
patients
CHA2
DS2
-VASc
score
–61%
5.34%
2.08%
Total
patient-years
HA
Effectiveness in stroke
Effectiveness in bleeding
Estimated based on
CHA2
DS2
-VASc score
Observed rate
in study
6
5
4
3
2
1
0
%
Estimated based on
HAS-BLED score
Observed rate
in study–59%
5.62%
2.30%
Total
patient-yearss
Total
patients
CHA2
DS2
-VASc
score
–61%
5.34%
2.08%
Total
patient-years
HAS-BLED
score
• 1,047 patients treated with ACP in 22 centres.
• Procedural success 97.3% (4.97% periprocedural major adverse events).
• Mean FU 13 months. Anual rates:
ACP registries

• 167 patients with AF treated with ACP, 12 centers, 2009-2013.
• Mean CHADS2 3.0, CHASDS2-VASC 4, HASBLED 3.
• Device success 94.6%.
• Procedural complications: cardiac tamponade 1.2%, device embolization 0.6%.
Table 3 shows observed events and CHADS2, CHA2DS2-VASc
and HAS-BLED-predicted events at 12 and 24 months
(expressed as annual event rates, 290 patients/year).
Significant differences in stroke events were observed during
the first year, whereas major bleeding events were only observed
during the second year. Tables 4 and 5, respectively, show the
comparative reduction in stroke following LAA occlusion,
located over the upp
lateral ridge; they a
respond well to trea
for 2 weeks. Once t
mation is virtually n
In this series, thro
around 8% of patie
from 5% to 17% de
the TOE follow-up
thrombus).5 12–19
M
when dual antiplatel
2 months, and usua
course of enoxaparin
implantation antithr
In the PROTECT A
was administered fo
other studies, DAPT
further 3 months w
good results with D
nite ASA18
suggestin
coumarol or warfari
One of the mos
reduced incidence o
the first and second
drugs. Bleeding at 2
Table 2 Raw clinical events and echocardiographic findings
during follow-up in 158 successfully implanted patients
Clinical events
Death 17 (10.8%)
Major bleeding 9 (5.7%)
Minor relevant bleeding 7 (4.4%)
Total bleeding events 16 (10.1%)
Stroke/TIA 7 (4.4%)
Some event 30 (19.0%)
Echocardiographic findings
Device thrombus 13 (8.2%)
Small residual ASD 18 (11.4%)
Leak 13 (8.2%)
ASD, atrial septal defect; TIA, transient ischaemic attack.
López Mínguez JR, et al. Heart 2015;101:877–883. doi:10.1136/heartjnl-2014-306332
Lopez-Minguez JR, et al. Heart. 2015;101:877-83.
IBERIAN registry
Less than
expected

What do we need?
Candidates for anticoagulation: RCT vs NOCA.
Not candidates for anticoagulation:
• RCT vs no anticoagulation.
New devices: head-to-head trials.
Anti-thrombotic therapy: RCT vs DAPT.

Stroke or systemic embolic events
Major bleeding
Ruff CT, et al. Lancet 2014;383: 955-962.
LAAC vs NOCA
Now, NOCA and not vK antagonists, are the standard of care in AF

NCT02426944
n = 400 patients with NVAF
LACC vs NOCA: PRAGUE-17
- History of significant bleeding even in the absence of anticoagulation
- cardioembolic event, which occurred on anticoagulation, or
- High risk profile (CHA2DS2-VASc ≥ 3 and a HAS-BLED ≥ 2).
Any of the following
1:1 randomization
LAAC (Amulet or Watchman) NOAC (any, preferably apixaban)
Stroke OR systemic cardioembolic event OR clinically significant bleeding OR
cardiovascular death OR procedure or device-related complications* at 12 months.

LAAC VS NOCA: NCT02549963
n = 200 patients with NVAF
1:1 randomization
LAAC (Watchman) NOAC (rivaroxaban)
All Stroke or Systemic embolism or Cardiovascular death at 2 yr
• Paroxysmal, persistent or permanent non-valvular atrial ﬁbrillation

• Eligible for LAAO and long-term rivaroxaban therapy

• Calculated CHA2DS2-VASc score of 2 or greater.

• No contraindications to aspirin, clopidogrel and novel oral anticoagulants.
NCT02549963

consistent among all patient subgroups examined.
Paradoxically, we observed a particular advantage for
LAA closure in patients with lower HAS-BLED scores,
possibly because the bleeding risk score also predicts
bleeding in patients who are not anticoagulated (18).
Patients with high HAS-BLED scores may, therefore,
FIGURE 2 Kaplan-Meier Curves for Major Bleeding
(A) Freedom from first major bleed from randomization to the end of follow-up (p ¼ 0.97). (B) Freedom from first major bleed from 8 days post-randomization to
the end of follow-up (the post-procedural period) (p ¼ 0.002). (C) Freedom from first major bleed from 45 days post-randomization to the end of follow-up)
(hazard ratio: 0.38; 95% confidence interval: 0.33 to 0.44; p < 0.001). (D) Freedom from first major bleed from 6 months post-randomization to the end of follow-up
(hazard ratio: 0.28; 95% confidence interval: 0.23 to 0.35; p < 0.001).
Values are n (%). Note that patients were randomly assigned to LAA closure or
warfarin therapy in a 2:1 fashion.
DAPT ¼ dual antiplatelet therapy; LAA ¼ left atrial appendage; OAC ¼ oral
anticoagulation.
PROTECT-AF: Benefit in terms of bleeding increases at longer FU.
Price MJ, et al. J Am Coll Cardiol Intv 2015;8:1925–32
LAAC IN PATIENTS UNSUITABLE FOR OAC

Main Line Health
Lankenau Heart Institute
Bleeding risks compound over patient lifetime
CHA2DS2-
VASc*
Score
Annual %
Stroke Risk
HAS-BLED** Score
Annual %
Bleed Risk
10-Year
Bleeding
Risk (%)***
0 0 0 0.9 8.6
1 1.3 1 3.4 29.2
2 2.2 2 4.1 34.2
3 3.2 3 5.8 45.0
4 4.0 4 8.9 60.6
5 6.7 5 9.1 61.5
* 2014 AHA / ACC / HRS Guidelines
** Lip. JACC (2011)
*** Assumes constant risk despite increasing age and bleeding risk is independent from bleeding risk in previous years
N
Patients at higher risk of bleeding should receive more beneﬁt.

LAAC IN PATIENTS UNSUITABLE FOR OAC: ASAP-TOO.
NCT02928497
n = 888 p with AF & contraindications to OAC
2:1 randomization
LAAC (Watchman) SAPT or no medication
CHA2DS2-VASc ≥ 2 unsuitable for oral anticoagulation.
• Safety: death, ischemic stroke, systemic embolism and complications
requiring major cardiovascular/endovascular intervention at 7 days.
• Efﬁcacy: time to ﬁrst event of ischemic stroke or systemic embolism at 5
years (2023).

LAAC AFTER ICB: STROKECLOSE
NCT02830152
n = 750 p with NVAF and ICB 1-6 mo before
2:1 randomization
LAAC (Amulet) Medical therapy
(OAC/NOCA/DAPT/SAPT/none)
• CHA2DS2VASc >2.

• Clinical and CT/MRI evidence of ICH 4 wk-6 mo (no vascular malformation or tumor)
Stroke (ischemic or haemorrhagic), systemic embolism, major bleeding,
and all cause mortality at 5-year (May 2022).

LAAC AFTER ICB: A3ICH
NCT03243175
n = 300 p with NVAF and ICB 1-6 mo before
1:1:1 randomization
LAAC (any) None
• CHA2DS2VASc ≥ 2.

• Spontaneous intracerebral haemorrhage documented with CT/MRI > 14 days before.
Major ischaemic and haemorrhagic events at 2 yr (12/2022).
Apixaban

LAAC AFTER CORONARY STENTING
n = 670 p with NVAF & coronary stenting
1:1:1 randomization
LAAC (ACP)

• Coronary artery disease requiring second-generation DES
Death, MI, stroke, systemic embolism, moderate/severe bleeding
(11/2020).
NCT02606552
Dabigatran+ASA
(+ Clopi 3 mo.)
Dabigatran+Clopi
(+ ASA 3 mo.)

LAAC AFTER CORONARY STENTING
n = 50 p with NVAF & coronary stenting
1:1 randomization
LAAC (Watchman)
• CHA2DS2VASc ≥ 2 & HAS-BLED ≥ 3.

• NSTEACS successfully treated with DES.
Bleeding acordingly to the GUSTO scale
NCT02492230
Warfarin +antiplatelet
(DAPT 45 d, clopi 6 mo.)

LAAC IN WITH RENAL FAILURE: WatchAFIB
NCT02039167
n = 300 p with NVAF & severe renal failure.
1:1 randomization
LAAC (Watchman)
• CHA2DS2VASc ≥ 2 & HAS-BLED ≥ 3.

• Severe to end-stage chronic kidney disease (eGFR < 30 ml/min by CKD-EPI formula).
moderate or severe bleedings at 2 yr (initially planned 06/2017)
Vitamin-K antagonists
(INR 2-3)

NCT03088098
LAAC IN PATIENTS UNDERGOING TAVI: TAVI/LAAO
n = 100 p with AF undergoing TAVI.
1:1 randomization
LAAC (ACP/Amulet)

• Transfemoral TAVR (Portico device).
Embolic events, major bleeding, CV death at 1 year (planned in 2018).
Conventional treatment

DEVICES OTHER THAN WATCHMAN OR AMULET
Study Device n Design End-point
NCT03147391 Lambre 66 Retrospective, single arm Ischemic stroke at 5 yr
LASSO-AF Aegis Sierra 30 Retrospective, single arm MACE at 30 days
LA-EU-1 Lambre 61 Prospective, single arm
SAE, stable device
placement, residual jet at 6
mo.
NCT02681042 Lariat 50 Single arm Succesful closure at 4 year
CLASS Ultrasept LAA 30 Single arm
Stroke, pericardial effusion,
device embolization/
thrombosis at 45 days
NCT02029014 Lambre 154 Single arm
Ischemic stroke, successful
sealing
OLAAC Occlutech 105 Single arm
Implantation success and
MACE at 1 year
NCT03204695 Wavecrest 65 Single arm Device success

Watchman
Amulet IDE WAVECREST2
Device Amulet WaveCrest
Clinicaltrials NCT02879448 NCT03302494
n 1,600 1,250
Randomization 1:1 1:1
Design Non-inferiority Non-inferiority
Risk
CHADS2 > 2 or
CHA2DS2-VASc ≥ 3
CHADS2 ≥ 2 or
CHA2DS2-VASc ≥ 3
End-point
Procedure-related
complications, all-cause
death, major bleeding at 1
year.
Procedure or device
complications at 45
days
vs vs
HEAD-TO-HEAD RCT

ANTI-THROMBOTIC TREATMENT AFTER LAAC
• Different devices have been used with different anti-thrombotic
regimens.
• In PROTECT-AF, 45% of patients had sub-therapeutic INR.
• and different levels of anticoagulation were not associated with
different clinical outcomes.
• Watchman trials without anticoagulation (e.g. ASAP) did not show
an increased risk of thrombotic events.
ADRIFT (NCT03273322)
LAAC (n=90)
Measure of prothrombin fragment
DAPT
Rivaroxaban
10 mg
Rivaroxaban
15 mg

´00 ´01 ´02 ´03 ´04 ´05 ´06 ´07 ´08 ´09 ´10 ´11 ´12 ´13 ´14 ´15 ´16 ´17 ´18
PLAATO
device
Watchman
CE mark
PREVAIL
(n=407)
PROTECT
AF (n=707)
RE-LY
(n=18,113)
ROCKET-AF
ACP CE
mark
WaveCrest
CE mark
ARISTOTLE
(n= 18,201)
ROCKET-AF
(n=14,264)
ENGAGE
(n=21,105)
AVERROES
(n=5,599)
PRAGUE-17
(n=400)
NCT02549963
(n=200)
vs NOAC
vs vKA or none
A3ICH
(n=300)
ASAP-TOO
(n=888)
STROKECLOSE
(n=750)
NCT02606552
(n=670)
NCT02492230
(n=50)
WatchAFIB
(n=300)
TAVI-LAAO
(n=100)

REFLEXIONES
• Creo firmemente que el cierre percutáneo de orejuela podría ofrecer
beneficio clínico a muchos pacientes con FA, especialmente aquéllos
con alto riesgo hemorrágico.
Es decir, que está claramente infrautilizado.
• Según la evidencia científica y las guías actuales simplemente
“puede” considerarse en pacientes con FA y contraindicaciones para
la anticoagulación.
• El concepto “contraindicaciones para anticoagulación” no está claro.
• Esta falta de evidencia hace que en ocasiones no sea fácil convencer
al cardiólogo clínico.
• Los estudios que están actualmente en marcha seguro que
conllevarán a modificaciones en las guías, pero sólo en los contextos
estudiados.

Fundación EPIC _ Left atrial appendage closure. Clinical evidence; where we are? By Raul Moreno

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