LAA Syllabus
2015-06-16
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6/16/2015
1
Data Behind LAA Closure –
This is Ready for Prime Time!
Vivek Y. Reddy, MD
Helmsley Trust Professor of Medicine
Director, Cardiac Arrhythmia Service
The Mount Sinai Hospital
vivek.reddy@mountsinai.org
Disclosures
•Grant support and/or Consultant:
–Boston Scientific Inc, Coherex Inc,
St Jude Medical Inc
(I have no equity interest in LAAC)
•I will be discussing non-approved
catheter devices.
Preventing Stroke in Atrial Fibrillation
Warfarin Intolerance / Non-Compliance
A.M.Gallagher J Thromb Haem 6:1500 (2008)
0
20
40
60
80
100
0 2 4 6
%
Years after starting treatment
40-64
65-69
Age
70-74
75-79
80-84
85
6/16/2015
2
Left Atrial Appendage Closure
Important Results from the Watchman Experience
1. Can a thrombus originate from outside the LAA?
2. Were the patients enrolled in the trials of
sufficient risk?
3. How safe is the Watchman implantation
procedure?
4. PROTECT AF/PREVAIL were randomized
against Warfarin … But now that we have
NOACs …
5. How cost-effective is LAAC?
Barbs Engage
LAA Wall
160 µ PET
fabric
Watchman
Left Atrial Appendage Closure
Important Results from the Watchman Experience
1. Can a thrombus originate from outside the LAA?
2. Were the patients enrolled in the trials of
sufficient risk?
3. How safe is the Watchman implantation
procedure?
4. PROTECT AF/PREVAIL were randomized
against Warfarin … But now that we have
NOACs …
5. How cost-effective is LAAC?
PROTECT-AF & PREVAIL
Design & Overview
•Randomized FDA-IDE Trials
–Can the WATCHMAN device replace
Warfarin?
–PREVAIL: At Least 25% new operators
•Efficacy Endpoints:
–1st Endpoint: Stroke / Systemic embolism
/ CV death (& Unknown)
–2nd Endpoint: Ischemic Stroke / Systemic
embolism (Post 7 days)
•Bayesian Statistical Plan
–Non-inferiority & Superiority
–Informative Prior?
•PROTECT-AF: (None)
•PREVAIL: Discounted data from
PROTECT-AF
Follow-Up
Non-Valvular AF
Risk Factors
Randomization (1:2)
Warfarin Watchman
Anticoagulation Regimen
•Implant to 6 weeks
–Warfarin
–Aspirin
•6 weeks to 6 months
–Clopidogrel
–Aspirin
•After 6 months
–Aspirin
6/16/2015
3
PROTECT AF
Superiority of Watchman over Warfarin
V.Reddy, H.Sievert, J.Halperin et al, JAMA, 312:1988 (2014)
Primary Endpoint
[ Stroke / SE / CV Death ] CV Death
Hemorrhagic Stroke: 85%↓↓
All-Cause Mortality vs Warfarin
Is a 34% Mortality Benefit by LAAC Plausible?
Watchman
Warfarin
V.Reddy, H.Sievert, J.Halperin et al, JAMA, 312:1988 (2014)
Ruff et al. Lancet, 383:955 (2014)
NOACs vs Warfarin
All-Cause Mortality
LAAC vs Warfarin
PROTECT-AF & PREVAIL
Combined Analysis
D.Holmes et al, JACC (in press)
HR p-value
Efficacy
0.79 0.22
All stroke or SE 1.02 0.94
Ischemic stroke or SE 1.95 0.05
Hemorrhagic stroke 0.22 0.004
CV/unexplained death 0.48 0.006
All
-cause death 0.73 0.07
Major
bleed, all 1.00 0.98
Major
bleeding, non procedure-related 0.51 0.002
Favors WATCHMAN Favors warfarin
Hazard Ratio (95% CI)
0.01 0.1 1 10
6/16/2015
4
PROTECT-AF & PREVAIL
Combined Analysis
HR p-value
Efficacy
0.79 0.22
All stroke or SE 1.02 0.94
Ischemic stroke or SE 1.95 0.05
Hemorrhagic stroke 0.22 0.004
CV/unexplained death 0.48 0.006
All
-cause death 0.73 0.07
Major
bleed, all 1.00 0.98
Major
bleeding, non procedure-related 0.51 0.002
Favors WATCHMAN Favors warfarin
Hazard Ratio (95% CI)
0.01 0.1 1 10
D.Holmes et al, JACC (in press)
Left Atrial Appendage Closure
Important Results from the Watchman Experience
1. Can a thrombus originate from outside the LAA?
2. Were the patients enrolled in the trials of
sufficient risk?
3. How safe is the Watchman implantation
procedure?
4. PROTECT AF/PREVAIL were randomized
against Warfarin … But now that we have
NOACs …
5. How cost-effective is LAAC?
Watchman Clinical Trials
Patients were at High Risk
0%
10%
20%
30%
40%
50%
0 1 2 3 4 5 6-9
CAP
PREVAIL
CAP2
Patients
(%)
CHA2DS2-VASc Score
96%
100%
100%
CHA2DS2-
VASc
Score ≥2
93%
PROTECT AF
0%
10%
20%
30%
40%
50%
0 1 2 3 4 5 6-9
6/16/2015
5
Modified HAS-BLED Score
> 90% Patients at Moderate/High Bleeding Risk
Study
Patients (%) with HAS-BLED* Score
Low Risk
(0)
Moderate Risk
(1-2) High Risk
(3+)
SPORTIF (
Ximelegatran
)
24.0 61.0 15.1
PROTECT
AF (N=707) 6.4 73.7 19.9
PREVAIL
(N=407) 1.7 68.6 29.7
CAP
(N=566) 2.8 61.0 36.2
CAP2
(N=579) 2.8 69.9 28.3
* Estimated –HAS-BLED Score retrospectively calculated. Labile INR and
Abnormal LFT were not prospectively collected. Therefore, maximum score
that WATCHMAN clinical trial patients could attain was 7.
Left Atrial Appendage Closure
Important Results from the Watchman Experience
1. Can a thrombus originate from outside the LAA?
2. Were the patients enrolled in the trials of
sufficient risk?
3. How safe is the Watchman implantation
procedure?
4. PROTECT AF/PREVAIL were randomized
against Warfarin … But now that we have
NOACs …
5. How cost-effective is LAAC?
Safety Events Across Trials
PROTECT AF, CAP, PREVAIL & CAP-1
Patients with Safety Event (%)
9.9%
4.8% 4.1% 4.1% 3.8%
0.0%
2.0%
4.0%
6.0%
8.0%
10.0%
12.0%
CAP PREVAIL CAP2
PROTECT AF
1st Half 2nd Half
N=232 N=231 N=566 N=269 N=579
6/16/2015
6
Bleeding: A Safety Issue with OAC
Less Bleeding after 6-mo Post-Implantation
V.Reddy et al, FDA Panel Presentation, October 2014.
Time (months)
Free of
Major
Bleeding
Event
(%)
660
46 180
845
50
60
70
80
90
100
0 7
Time (days)
Warfarin
+Aspirin Warfarin
+Aspirin Aspirin+
Clopidogrel
HR = 0.29
p<0.001
Aspirin
WATCHMAN
Warfarin
PROTECT-AF & PREVAIL Combined Analysis
Left Atrial Appendage Closure
Important Results from the Watchman Experience
1. Can a thrombus originate from outside the LAA?
2. Were the patients enrolled in the trials of
sufficient risk?
3. How safe is the Watchman implantation
procedure?
4. PROTECT AF/PREVAIL were randomized
against Warfarin … But now that we have
NOACs …
5. How cost-effective is LAAC?
Drug Use Since the Introduction of NOACs
Warfarin is Still the Most Commonly Used Drug
Jani, et al. Results from the NCDR-Pinnacle Registry ACC -2014
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
2011 Q1 2011 Q2 2011 Q3 2011 Q4 2012 Q1 2012 Q2 2012 Q3 2012 Q4
Total on Oral
Anticoagulation
Warfarin
NOACs
Anticoagulant Use in Patients with
NVAF and CHADS2≥ 2
n=25719 n=29194 n=31582 n=36490 n=67102 n=70667 n=70320 n=71396
40%
6/16/2015
7
NOACs are Excellent Medications
But Not for Everyone…
FDA Slide Deck. Dabigatran FDA Review from Panel Meeting 2010
RELY: Major Bleeding
w/ Anti-Platelet
0.0%
1.0%
2.0%
3.0%
4.0%
5.0%
6.0%
7.0%
NOAC
NOAC +
ASA/Clop
Preventing Stroke in Non-Valvular AF
Imputed Benefit of Different Strategies (vs Control)
-90%
-80%
-70%
-60%
-50%
-40%
-30%
-20%
-10%
0%
Stroke Reduction
(vs Placebo)
*
*
*
*
Reached statistical superiority relative to warfarin.
*
Left Atrial Appendage Closure
Important Results from the Watchman Experience
1. Can a thrombus originate from outside the LAA?
2. Were the patients enrolled in the trials of
sufficient risk?
3. How safe is the Watchman implantation
procedure?
4. PROTECT AF/PREVAIL were randomized
against Warfarin … But now that we have
NOACs …
5. How cost-effective is LAAC?
6/16/2015
8
Economic Analysis: Budget Impact
Watchman vs Dabigatran vs Warfarin
S.L.Amarosi et al, Europace, 16:1131 (2014)
Amplatzer Cardiac Plug Registry
Efficacy
Tzikas A et al, EuroIntervention (in press)
5.62%
2.30%
0%
1%
2%
3%
4%
5%
6%
Annual Stroke Risk
Effectiveness in Stroke Reduction
vs Estimated
Estimated
based on
CHA2DS2-VASc
Score
Observed rate
in study
-59%
Total Patients Total Patient Years CHA2DS2-VASc Score
1001 1349 4.43
Estimated Stroke Rate per
CHA2DS2-VASc
Actual Annual Stroke Rate
(N strokes + TIA)
5.62% 2.30% (31)
5.34%
2.08%
0%
1%
2%
3%
4%
5%
6%
Annual Bleeding Risk
Effectiveness in Bleeding
Reduction vs Estimated
Estimated
based on
HAS-BLED
Score
Observed rate
in study
-61%
Total Patients Total Patient Years HAS-BLED
Score
1001 1349 3.12
Estimated Bleeding Rate per
HAS-BLED
Actual Annual Bleeding Rate
(N major bleeds)
5.34% 2.08% (28)
Amplatzer
•~40% of patients are not protected against stroke w/ OACs
• “Local” therapy with LAA closure is comparable to Warfarin
–LAAC less effective in preventing Ischemic Strokes, but balanced by
fewer Hemorrhagic Strokes
–Over 50% reduction in Disabling Strokes
–Over 50% reduction in Cardiovascular Mortality
•Safety improves with Operator Experience
–Tamponade Rate: 5% [PROTECT AF] 1-2% [CAP/PREVAIL/CAP-2]
Final Thoughts
LA Appendage Closure & Stroke Prevention
6/16/2015
9
The Watchman Device
FDA Labeling
Watchman is indicated to reduce the risk of
thromboembolism from the left atrial appendage in
patients with non-valvular atrial fibrillation who
are:
1. At increased risk for stroke and systemic embolism based
on CHADS2 or CHA2DS2-VASc scores
2. Are suitable for warfarin
3. And have an appropriate rationale to seek a non-
pharmacologic alternative to warfarin, taking into
account the safety and effectiveness of the device
compared to warfarin.
Watchman: FDA Labeling
Device Patient Selection Considerations
A history of major bleeding
while taking therapeutic
anticoagulation therapy
The patient’s prior experience
with oral anticoagulation (if
applicable)
A medical condition,
occupation, or lifestyle placing
the patient at high risk of major
bleeding secondary to trauma
The presence of indication(s)
for long-term warfarin use,
other than non-valvular atrial
fibrillation
Overall medical status
Suitability for percutaneous,
trans-septal procedures
Ability to comply with the
recommended post-Watchman
device implant pharmacologic
regimen
Rationale for seeking an
alternative to warfarin: Factors to consider for
Watchman implantation:
08/06/2015
1
VuMedi CME Webinar: LAA closure in 2015
London –16 June 2015
LAA Closure: The Epicardial Approach
Dr John P Foran
Consultant Cardiologist
Royal Brompton Hospital –London, GB
Components of the Lariat LAA closure device
for the percutaneous epicardial placement of a pre-tied suture loop
Left Atrium
Left Atrial
Appendage
Lariat LAA closure animation
08/06/2015
2
The Next Generation LARIAT + Device
Lariat +
snare width increased from
40 mm → 45 mm
Improved torque-ability of catheter due to
stainless steel wire braid on catheter shaft
“L”Marker
Platinum-Iridium
“L”Marker
Pre CT 45-day Post CT
LAA No LAA
Lariat LAA ligation closure may result in
a permanent transmural lesion
LAA
LA
LA
LAA
1 cm
LAA Suture Endo
Endo
LA
Lariat LAA ligation closure may result in
a permanent transmural lesion
Bartus et al Circ Arrhythmia 2014; 7: 764-767
08/06/2015
3
Lariat Device –Initial clinical experience
K Bartus et al JACC 2013; 62: 108-118
Micropuncture telescopic 2-piece needle
pericardial access technique
LAA Closure: The Epicardial Approach
Discussion points:
•Truly OAC contraindicated patients
•Planning CTLA
•Novel µ-puncture telescopic 2-piece needle
•Third generation Lariat + device
•Initial European Experience with Lariat + (n=86)
86/86 acute closure / n=2 (2.3%) complications / 97% (30/31) complete closure at 3/12 f/u
•No device related concerns
08/06/2015
4
6/11/2015
1
Sameer Gafoor, Horst Sievert, Patrick Böhm,
Ilona Hofmann, Laura Vaskelyte, Stefan Bertog
CardioVascular Center Frankfurt - CVC
Frankfurt, Germany
Endocardial Devices
VuMedi Webinar
12min
Stroke Prevention in AF
Patients with the WATCHMAN
(Organized by CVRF
and Supported by Educational
Grant from Boston Scientific)
Coronary Arena, Level 1
: Yangsoo
Jang, Young
-
Hoon Kim
: Rak Kyeong
Choi, June
Hong Kim,
-
Sun Kim,
-
Jang Kim,
Hwan Lee,
Byoung
Nam, Cheol
Woong Yu
Latest Update
on LAAC and
Its Clinical
Evidence
Lecturer: Saibal
Kar
Place of
LAAC in the
Era of New
OATs
Lecturer: Horst
Sievert
Requirements
for a Successful
LAAC Program
Lecturer:
Matthew Price
WATCHMAN
Single Center
Experience
Lecturer: Teguh
Santoso
Panel
Discussion -
CardioVascular Center Frankfurt CVC
Indications and
indications
Atrial fibrillation is one of the most important stroke
causes, especially in the elderly
Framingham Study, Wolf, 1991
0
5
10
15
20
25
30
35
40
50-59 60-69 70-79 80-89
Age
%
6/11/2015
2
Anticoagulation in AF
Randomised Trials
0
2
4
6
8
10
12
14
AFASAK BAATAF SPAF-I CAFA SPINAF EAFT
Control Warfarin
*p<0.05
–71%* –86%* –69%* –52% –79%*
–66%*
Anticoagulation is
effective, …
… but unfortunately it does not
always work in clinical practice…
… not with warfarin and not with
newer drugs
•Any localized or general physical
condition in which the hazard of
hemorrhage might be greater than
the potential clinical benefits of
anticoagulation
•Any personal circumstance in which
the hazard of hemorrhage might be
greater than the potential clinical
benefits of anticoagulation
•Pregnancy
•Hemorrhagic tendencies
•Blood dyscrasias.
•Recent or contemplated surgery of
central nervous system
•Recent or contemplated surgery of
the eye
•Recent or contemplated traumatic
surgery resulting in large open
surfaces
•Gastrointestinal bleeding
•Genitourinary tract bleeding
•Respiratory tract bleeding
•Cerebrovascular hemorrhage
•Cerebral aneurysms
•Dissecting aorta
•Pericarditis
•Pericardial effusions
•Bacterial endocarditis
•Threatened abortion
•Eclampsia
•Preeclampsia
•Inadequate laboratory facilities
•Unsupervised patients
•Senility
•Alcoholism
•Psychosis
•Lack of patient cooperation
•Spinal puncture
•Other diagnostic procedures with
potential for uncontrollable bleeding
•Therapeutic procedures with
potential for uncontrollable bleeding
•Major regional anesthesia
•Lumbar block anesthesia
•Malignant hypertension
6/11/2015
3
CardioVascular Center Frankfurt CVC
Lone Atrial Fibrillation
0%
20%
40%
60%
80%
100%
<65 65-74 75-79 >80
not on Coumadin
on Coumadin
Stafford and Singer, Arch Int Med, 1996
Only about 1/3 of all eligible
patients are taking Coumadin
CardioVascular Center Frankfurt CVC
Lone Atrial Fibrillation
0%
20%
40%
60%
80%
100%
<65 65-74 75-79 >80
not on Coumadin
on Coumadin
Stafford and Singer, Arch Int Med, 1996
CardioVascular Center Frankfurt CVC
CHA2DS2-VASc Score Treatment
0 or 1 and female none
≥ 1 Coumadin or NOAC
0%
3%
5%
8%
10%
13%
15%
18%
0.0%
1.3%
2.2%
3.2% 4.0%
6.7%
9.8% 9.6%
6.7%
15.2%
0 1 2 3 4 5 6 7 8 9
Condition/Risk Factor
Points
C
Congestive heart failure
1
H
Hypertension
1
A
2
Age ≥75 years
2
D
Diabetes Mellitus
1
S
2
Previous
stroke or TIA 2
V
Vascular
disease 1
A
Age 65
-74 years 1
Sc
Sex (female gender)
1
European Society of Cardiology Guidelines 2012
Annual Risk of Stroke
CHA2DS2VASc Score
Risk of Stroke
•CHA2DS2VASc, developed by Lip et al, is a refinement of the older CHADS2
Score which includes additional stroke risk factors and puts greater emphasis on
age as a risk factor1
CHA2DS2VASc
1. Lip GY et al, Chest 2010;137(2):263-72
6/11/2015
4
CardioVascular Center Frankfurt CVC
Is there another option
to reduce this?
CardioVascular Center Frankfurt CVC
Where do thrombi form?
Setting N Appendage Percent LA Body Percent Reference
TEE 317 66 21 1 0.3 Stoddard; JACC, 1995
TEE 233 34 15 1 0.4 Manning; Circ, 1994
Autopsy 506 35 7 12 2.4 Aberg; Acta Med Scan, 1969
TEE 52 2 4 2 3.8 Tsai; JFMA, 1990
TEE 48 12 25 1 2.1 Klein; Int J Card Image, 1993
TEE & Operation 171 8 5 3 1.8 Manning; Circ, 1994
SPAF III TEE 359 19 5 1 0.3 Klein; Circ, 1994
TEE 272 19 7 0 0.0 Leung; JACC, 1994
TEE 60 6 10 0 0.0 Hart; Stroke, 1994
Total 2018
Total Thrombus 222 201 90.5 21 9.5
Blackshear and Odell, Ann Thoracic Surgery 1996
Who among
us has not
seen this?
Or at least
been tested
on it?
6/11/2015
5
Stroke Prophylaxis: LAA Closure
Blackshear and Odell, Ann Thoracic Surgery 1996
Where is the
evidence?
CardioVascular Center Frankfurt CVC
Trials to know…
•PROTECT AF
•CAP
•PREVAIL
•ASAP
6/11/2015
6
CardioVascular Center Frankfurt CVC
PROTECT AF Trial
•Prospective, randomized study of WATCHMAN LAA Device vs.
Long-term Warfarin Therapy
•2:1 allocation ratio device to control
•800 Patients enrolled from Feb 2005 to Jun 2008
-Device Group (463)
-Control Group (244)
-Roll-in Group (93)
•59 Enrolling Centers (U.S. & Europe)
•Follow-up Requirements
-TEE follow-up at 45 days, 6 months and 1 year
-Clinical follow-up biannually up to 5 years
-Regular INR monitoring while taking warfarin
CardioVascular Center Frankfurt CVC
PROTECT-AF Trial
Study Timeline
Holmes ACC 2013
CardioVascular Center Frankfurt CVC
PROTECT-AF Study
Endpoints
•Efficacy endpoint
-All stroke –ischemic or hemorrhagic
•Deficit with symptoms more than 24 hours
•Symptoms less than 24 hours confirmed by CT
or MRI
-CV and unexplained death
•includes sudden death, MI, CVA, arrhythmia,
and heart failure
-Systemic Embolization
6/11/2015
7
CardioVascular Center Frankfurt CVC
PROTECT-AF Study
Endpoints
•Safety Endpoint
-Device embolization requiring retrieval
-Pericardial effusion requiring intervention
-Cranial bleeds and GI bleeds
-Any bleed requires more than 2U PRBC
CardioVascular Center Frankfurt CVC
CardioVascular Center Frankfurt CVC
Primary efficacy endpoint
Significantly more events in the control group
Watchman is superior to warfarin (p<0.05)
Hazard Ratio 0.6
6/11/2015
8
CardioVascular Center Frankfurt CVC
Primary safety endpoint
Watchman is non-inferior to warfarin
CardioVascular Center Frankfurt CVC
Ischemic stroke
CV Mortality
All-cause mortality
RR 1.26, p=NS
RR 0.40 p=0.005
RR 0.66 p=0.04
CardioVascular Center Frankfurt CVC
Safety endpoint
6/11/2015
9
CardioVascular Center Frankfurt CVC
Issues with the
PROTECT-AF trial
•PROTECT-AF had low risk patients
(34% of subjects had CHADS2 score of
1
•Adjunctive antiplatelet therapy with
aspirin and clopidogrel enrolled in the
trial
•Acute safety events: 56% of primary
safety events in device group occurred
on day of procedure
CardioVascular Center Frankfurt CVC
Continued Access
Registry
•Continued access to the Watchman
device for a subset of the PROTECT-AF
study investigators
•Nonrandomized
•Same inclusion and exclusion criteria as
PROTECT AF
•460 patients at 26 centers between
August 2008-April 2010
CardioVascular Center Frankfurt CVC
CAP Registry
6/11/2015
10
CardioVascular Center Frankfurt CVC
CAP Registry results
•Serious pericardial effusion rate down to
2.2%
•No procedure –related stroke
•Relative risk reduction of 56% (p=0.002)
in procedure or device-related safety
events
•Relative risk reduction of 58% (p=0.014)
in serious pericardial effusions
CardioVascular Center Frankfurt CVC
PROTECT-AF
early vs. late
Reddy, Circulation 2011
With increased operator experience,
the procedure related adverse
events and serious pericardial
effusions were reduced significantly.
Peri-procedural strokes were
eliminated
1,1 0,7
0
0
1
2
3
4
5
PROTECT AF Early PROTECT AF Late CAP
Incidence %
Procedure Related Stroke
Performance –Learning Curve Effect
PROTECT-AF vs. CAP
10
5,5
3,7
0
5
10
15
PROTECT AF EarlyPROTECT AF Late CAP
Incidence %
Procedure/Device Related Safety Adverse
Event Within 7 Days
6,3
3,7
2,2
0
2
4
6
8
10
PROTECT AF Early PROTECT AF Late CAP
Incidence %
Serious Pericardial Effusion Within 7 Days
6/11/2015
11
CardioVascular Center Frankfurt CVC
Reasons for
PREVAIL study
•Concerns for early PROTECT-AF stafety
-Many pericardial effusions and procedure
related strokes
-Many Watchman patients did not receive
assigned treatment
-Not tested with new operators
•Second randomized trial needed to confirm
late PROTECT-AF and CAP results
•More warfarin compliance needed
•Change the noninferiority margin
CardioVascular Center Frankfurt CVC
PREVAIL study
•Prospective multicenter 2:1 randomized
study
•Faster time from randomization to
implant
•More new implanters
•Different primary endpoints
-1st primary endpoint –same as PROTECT
AF
-2nd primary endpoint
•Ischemic stroke and systemic embolism >7
days post randomization
CardioVascular Center Frankfurt CVC
PREVAIL
inclusion criteria
•CHADS2 criteria –calculated score of 2
or greater
•Took people that would not be
candidates for aspirin therapy alone,
i.e.,
-CHADS1 criteria of 1 or greater if
•Age >75 or older
•Baseline LVEF 30-35%
•Age 65-74 and has diabetes or CAD
•65 or greater with documented CHF
6/11/2015
12
CardioVascular Center Frankfurt CVC
PREVAIL
CardioVascular Center Frankfurt CVC
PREVAIL patients were
different
CardioVascular Center Frankfurt CVC
Implant success
improved
6/11/2015
13
CardioVascular Center Frankfurt CVC
Vascular complications
decreased
CardioVascular Center Frankfurt CVC
Pericardial effusions requiring intervention
decreased
CardioVascular Center Frankfurt CVC
Endpoints
•Primary endpoint: 7 day death ischemic
stroke, systemic embolism and procedure or
device-related complications requiring major
cv endovascular intervention
-Improved procedural implant success
-Decreased composite vascular complications
-Decreased procedural stroke rate
-Decreased perforations requiring surgical repair
-Little difference in outcome between new and old operators
6/11/2015
14
CardioVascular Center Frankfurt CVC
Endpoints
•2 endpoint: composite endpoint of stroke,
systemic embolism and CV death
-Control group had low event rates compared to past
-Similar low event rate
-Although event rates similar, did not meet non-inferiority criterion
CardioVascular Center Frankfurt CVC
In addition, improved
warfarin discontinuation
CardioVascular Center Frankfurt CVC
FDA Approval for
•Nonvalvular atrial fibrillation
•Increased risk for stroke and systemic
embolism based on CHADS2 or
CHADS2VASc score AND
•Deemed by physicians to be suitable for
warfarin AND
•Have appropriate rationale to seek a
non-pharmacologic alternative to
warfarin
6/11/2015
15
CardioVascular Center Frankfurt CVC
That’s nice, except for a
slight intercontinental
difference
Camm EHJ 2012
CardioVascular Center Frankfurt CVC
Camm EHJ 2012
CardioVascular Center Frankfurt CVC
So what did they
recommend?
ESC 2012 Update Afib GuidelinesCamm EHJ 2012
6/11/2015
16
CardioVascular Center Frankfurt CVC
Why did they do that?
•There are more devices available in
Europe than in the US
Yu Nature Reviews
Cardiology 2013
CardioVascular Center Frankfurt CVC
Why did they do that?
•More studies available in Europe with
more patients, mostly for
contraindicated for anticoagulation
Lopes-Minguez Heart 2015
CardioVascular Center Frankfurt CVC
ASAP trial for Watchman
•150 patients with Afib at 4 centers
•Not candidates for oral anticoagulation
Reddy JACC 2013
6/11/2015
17
CardioVascular Center Frankfurt CVC
ASAP trial
Reddy JACC 2013
CardioVascular Center Frankfurt CVC
ASAP trial
Expected rate with
CHADS2 7.3%
Expected rate if use
aspirin and clopidogrel
5.0%
Actual seen rate of
ischemic stroke 1.7%
Reddy JACC 2013
CardioVascular Center Frankfurt CVC
Other
possible/(upcoming)
indications
•Patients with contraindication to
anticoagulation
•As complement to anticoagulation (e.g.,
patient now requires PCI)
•As adjunct to ablation of atrial fibrillation
Meier, Sievert et al. Eurointerv 2014
6/11/2015
18
CardioVascular Center Frankfurt CVC
Meier, Sievert et al. Eurointerv 2014
PLAATO™ Occluder
LA
LAA
Nitinol
frame
ePTFE
Membrane Hooks
•Procedure time 85 min
•Coumadin off since 2001
•Had his 84th birthday in Jan
2013
•Zero bleeding
•Zero embolic events
First LAA closure Aug 30, 2001
No
complication
s
Participated
in other FIM
trials
6/11/2015
19
CardioVascular Center Frankfurt CVC
PLAATO
•Technical success rate 94%
•Periprocedural MAE 5%
•No device related complications
beyond 30 days
•Stroke risk reduction 65%
•FU up to 11 yrs
LAA Closure
Endocardial Epicardial
•PLAATO
•Watchman
•ACP Amulet
•Coherex
•Sideris Patch
•Occlutech
•pfm Medical
•Lifetech
•Cardia
•SentreHeart
•AEGIS
•AtriCure
•Medtronic
Sideris
Patch
Watchman Occluder
Current trials with the
Watchman Device:
•PROTECT AF (System for
Embolic PROTECTion in Patients
with Atrial Fibrillation)
•CAP (Continued Access
PROTECT AF Registry)
•ASAP (ASA Plavix Feasibility
Study)
•Nitinol
•PET membrane
•Hooks
•21, 24, 27, 30,
33 mm
CE mark
6/11/2015
20
Watchman Implantation
•LAA diameter in TEE
19 mm
Maximum
measured
LAA ostium
(mm)
Implant
diameter
(mm)
17 -19.5 21
20 - 22.9 24
23 - 25.9 27
26 –28.9 30
29 –31.9 33
•device selection according
to measurements •Implantation of 21mm
Watchman Occluder
Watchman Implantation
CardioVascular Center Frankfurt CVC
PROTECT AF:
Primary Efficacy Endpoint:
Stroke, Death, Systemic Embolization
Watchman is superior to warfarin (p<0.05)
Hazard Ratio 0.6
6/11/2015
21
Intention-to-Treat:
All-Cause Mortality
Hazard Ratio with Watchman, 0.66
(95% CI, 0.45 –0.98)
P = 0.0379
Primary Safety Endpoint:
device embolization, pericardial effusion, severe bleeding
Regarding safety, Watchman is non-inferior to warfarin
CardioVascular Center Frankfurt CVC
Amplatzer Cardiac Plug
•Lobe diameter 16-30mm
•Lobe length 6.5mm
•Disk diameter 20-36mm
•9, 10 or 13F sheath
6/11/2015
22
CardioVascular Center Frankfurt CVC
Amplatzer Cardiac Plug
Post-Market EU Registry
•Prospective study
•100 % monitored
•Independent adjudication of AEs
•15 European centers
•N = 204
•Follow-up: 1214 patient months
Patients Consented
N = 206
Failed to Implant N = 7
(Device withdrawn in 5)
Consented Screen Failures
N = 2
Device Implanted
N = 197
1 month follow up
N = 191
6 month follow up
N = 183
Patients Enrolled
N = 204
Technical success 96.6%
Amplatzer Cardiac Plug
Post-Market EU Registry
Device/Procedure Related
Safety Events
N=204
≤7 Days
Post Procedure >7 days
Post Procedure Total
Peri-procedural Stroke /
TIA* 0 (0.0%) 0 (0.0%) 0 (0.0%)
Serious Pericardial Effusion 3 (1.5%) 0 (0.0%) 3 (1.5%)
Device Embolization 3 (1.5%) 0 (0.0%) 3 (1.5%)
Device Related Thrombus 0 (0.0%) 5 (2.4%) 5 (2.4%)
Total Safety Events 6 (2.9%) 5 (2.4%) 11 (5.4%)
* The stroke/TIA is reference to device or procedure related strokes as adjudicated by the AE
Review Committee.
6/11/2015
23
CardioVascular Center Frankfurt CVC
Amulet
•Pre-loaded
•Recessed end screw
•Larger disc diameter
•Longer lobe length
•Longer waist length
•Larger sizes up to 34mm
•Stiffer stabilizing wires
(.0065)
•More stabilizing wires on
larger devices
CardioVascular Center Frankfurt CVC
Increased Stability
•More stabilizing wires in larger devices
increased stability
ACP Amulet
CardioVascular Center Frankfurt CVC
Flexible Delivery Cable
•Delivery cable includes an 0.014” inner wire
•Enables visualization of final device
placement prior to release
6/11/2015
24
Coherex WaveCrest
•Retractable anchors
•ePTFE occluder material
is occlusive and non-
thrombogenic
•Distal contrast injection
•to assess stability
•to assess occlusion
•3 sizes (22, 27, 32mm)
.
•20
points
of
anchori
ng
CE mark Aug 2013
The Coherex WAVECREST I Trial
Gen 1.3
enrolled
patients
n = 63
implant
successful
n=61
implant
unsuccessful
n=2
per protocol
population
n=60
lost to follow
up n=1
Primary Efficacy Endpoint
intent to treat
(n = 63)
per protocol1
(n=60)
45 day closure
258 (92%) 58 (97%)
1) per protocol: successful device implant & 45 day transesophageal
echo suitable for interpretation by echo core lab
2) closure: no residual flow >3 mm
The Coherex WAVECREST I Trial
6/11/2015
25
Primary Safety Endpoint
MAEs through 45 Days
Enrolled population
N = 63
Device embolization 0
Pericardial effusion 0
Stroke or TIA 0
Device associated thrombus 0
The Coherex WAVECREST I Trial
6/4/2015
1
©2012 MFMER | slide-1
Future of LAA Closure
David R. Holmes, Jr., M.D.
Mayo Clinic, Rochester
VuMedi Webinar
June 2015
©2012 MFMER | slide-2
Presenter Disclosure Information
David R. Holmes, Jr., M.D.
“Future of LAA Closure”
The following relationships exist related to this presentation:
Both Mayo Clinic and I have a financial interest in
technology related to this research. That technology
has been licensed to Boston Scientific.
©2014 MFMER | 3392826-3
Disappearing LAA Thrombus Resulting in Stroke
Parekh A, Ezekowitz M et al: Circ 114:e513, 2006
6/4/2015
2
©2012 MFMER | slide-4
LAA Occlusion and Stroke Prevention
What are the Issues
•Stroke risk
•Pathophysiology of stroke
•Bleeding and drug discontinuation remains
a problem with OAC therapies (new and old)
•Site specific therapy makes intuitive sense
•Does it work?
•Which patients
©2012 MFMER | slide-5
How Big is the Problem?
•AF is the most common arrhythmia
•Affects more than 3 million individuals in the
U.S.
•Projected to increase to 16 million by 2050
•Lifetime risk in men and women >40 is 1 in 4
•Patients with AF have a 5-fold higher risk of stroke
•Over 87% of strokes are thromboembolic
•Cardioembolic strokes result in highest
morbidity and mortality
•Recurrence rates are high
•Both AF and Stroke increase as we grow older
©2012 MFMER | slide-6
Location of Thrombi in Left Atrium
020 40 60 80 100
Stoddard: JACC, 1995
Manning: Circ, 1994
Aberg: Acta Med Scan, 1969
Tsai: JFMA, 1990
Klein: Int J Card Imag, 1993
Manning: Circ, 1994
Klein: Circ, 1994
Leurig: JACC, 1994
Hart: Stroke, 1994
Total
Blackshear et al: Ann Thoracic Surg 61, 1996
Location frequency (%)
Left atrial appendage Left atrium
91% in LAA
6/4/2015
3
©2014 MFMER | 3393308-7
Nonvalvular Atrial Fibrillation
Stroke Prevention
•Warfarin most commonly used
•Reduces stroke by 64%
•Severely underutilized
•Even after AF stroke only 30-70% of patients
are anticoagulated
•At 3 years after initiation of warfarin ~ 50% of
patients discontinue therapy
•Clinical reality
•“VKA therapy only achieves a fraction of its
evidence-based potential”
Lewalter T et al: Europace 16:626-630, 2014
©2014 MFMER | 3392826-8
CHA2DS2-VASc Refines Stroke Risk
Determination in AF Patients
Risk Factor Score
Prior stroke or TIA 2
Age ≥75
Age 65-74 2
1
Hypertension 1
Diabetes mellitus 1
Heart failure 1
Vascular disease 1
Female sex 1
CHA2DS2-VASc Risk Criteria
0
5
10
15
20
25
0 1 2 3 4 5 6 7-9
CHADS2-VASc Score
One Year Stroke Risk
Mason PK: Am J Medicine, 2012
©2014 MFMER | 3392826-9
HAS-BLED Stratifies Bleeding Risk
on Warfarin
Condition Points
Hypertension 1
Abnormal liver and
renal function
(1 point each) 1 or 2
Stroke 1
Bleeding 1
Labile INR 1
Age >65 1
Drugs or alcohol
(1 point each) 1 or 2
HAS-BLED
0
5
10
15
0 1 2 3 4 5
HAS-BLED Score
Incidence of Major Bleeding
Events (% per year)
Roldan V: Chest, 2013
6/4/2015
4
©2012 MFMER | slide-10
Bleeding Stroke
©2014 MFMER | 3393308-11
Nonvalvular Atrial Fibrillation
Stroke Prevention
•NOACS have been widely tested as an alternative
to warfarin
•Found to have less ICH than warfarin
•Still not widely adopted
•Cost
•Lack of antidotes
•Dosing
•Bleeding hazard –GI bleeding may even be
increased
Lewalter T et al: Europace 16:626-630, 2014
©2012 MFMER | slide-12
NOACS versus Warfarin
•NOACS:
•Significant ↓ in all cause mortality
•RR 0.90, 95% CI 0.85-0.95
•Significant ↓ in ICH
•RR 0.48, 95% CI 0.39-0.59
•Significant ↑ in GI bleeding
•RR 1.25, 95% CI 1.01-1.55
Ruff et al: Lancet 383:955-62, 2014
6/4/2015
5
©2012 MFMER | slide-13
LAA Closure for Stroke Prevention in
Non-Valvular AF
Bergmann MW et al: EuroIntervention 2014;10:497-504
©2012 MFMER | slide-14
PROTECT AF: Long-Term Efficacy Results
(2,621 Patient-Years of Follow-Up)
Event rate
(per 100 pt-yr)
Rate ratio
(95% Crl)
Posterior
probabilities
WATCHMAN
n=463 Control
n=244 Non-
inferiority Superiority
Primary efficacy 2.3 3.8
0.60 (0.41, 1.05)
>0.999 0.960
Stroke (all) 1.5 2.2
0.68 (0.42, 1.37)
0.999 0.825
Ischemic 1.4 1.1
1.26 (0.72, 3.28)
0.779 0.147
Hemorrhagic 0.2 1.1
0.15 (0.03, 0.49)
0.999 0.999
Systemic
embolism 0.2 0.0 NA NA NA
Death (CV &
unexplained) 1.0 2.4
0.40 (0.23, 0.82)
>0.999 0.995
PAF
CAP PREVAIL
©2012 MFMER | slide-15
PROTECT AF: Long-Term Results
(2,621 Patient-Years of Follow-Up)
Event rate
(per 100 pt-yr)
Rate ratio
(95% Crl)
Posterior
probabilities
WATCHMAN
n=463 Control
n=244 Non-
inferiority Superiority
Primary efficacy 2.3 3.8
0.60 (0.41, 1.05)
>0.999 0.960
Stroke (all) 1.5 2.2
0.68 (0.42, 1.37)
0.999 0.825
Ischemic 1.4 1.1
1.26 (0.72, 3.28)
0.779 0.147
Hemorrhagic 0.2 1.1
0.15 (0.03, 0.49)
0.999 0.999
Systemic
Embolism 0.2 0.0 n/a n/a n/a
Death (CV &
unexplained) 1.0 2.4
0.40 (0.23, 0.82)
>0.999 0.995
PAF
CAP PREVAIL
6/4/2015
6
©2012 MFMER | slide-16
“I got a bad feeling about this, Harriet.”
©2012 MFMER | slide-17
Safety Events:
PROTECT AF, CAP, PREVAIL
9.9
4.8 4.1 4.2
0
2
4
6
8
10
12
1st half 2nd half CAP PREVAIL
Patients (%)
CAP
Registry PREVAIL
PROTECT
AF
n=232 n=231 n=566
PROTECT AF
n=269
©2014 MFMER | 3392826-18
PROTECT AF/PREVAIL Meta-Analysis:
WATCHMAN Comparable to Warfarin
HR P
Efficacy
0.79 0.22
All stroke or SE 1.02 0.94
Ischemic stroke or SE 1.95 0.05
Hemorrhagic stroke 0.22 0.004
Ischemic stroke or SE >7 days 1.56 0.21
CV/unexplained death 0.48 0.006
All
-cause death 0.73 0.07
Major
bleed, all 1.00 0.98
Major
bleeding, non procedure-related 0.51 0.002
0.01 0.1 1 10
Hazard Ratio (95% CI)
Favors WATCHMAN Favors warfarin
6/4/2015
7
©2012 MFMER | slide-19
LAA Occlusion and Stroke Prevention
What are the Issues
•Stroke risk
•Pathophysiology of stroke
•Bleeding and drug discontinuation remains
a problem with OAC therapies (new and old)
•Site specific therapy makes intuitive sense
•Does it work?
•Which patients
©2012 MFMER | slide-20
Aspirin and Plavix®Registry (ASAP)
The ASAP registry is a non-
randomized feasibility study
designed to evaluate if the
WATCHMAN®Device is a safe
and effective treatment for
people unable to take warfarin
•AF patients who are
contraindicated or intolerant of
warfarin have few options for
thromboembolic prophylaxis
•Patients may be treated with
aspirin and/or clopidogrel; this
treatment paradigm has a
higher stroke risk than warfarin
0
2
4
6
8
10
12
PRIOR TIA PRIOR STROKE
Stroke risk (%)
Annual risk of stroke with
secondary prevention of aspirin
or warfarin
7%
3%
11%
4%
Aspirin
Warfarin
The WATCHMAN Device is not approved for patients contraindicated to OACs
©2012 MFMER | slide-21
Results
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
Expected and Observed Stroke Rates (per 100 patient-years)
Observed rate of ischemic stroke represents a 77%
reduction from the expected event rate
Expected,
based on CHADS2score
Expected,
if Clopidogrel was used
throughout follow-up
Observed rate in ASAP
7.3%
5.0%
1.7%
77%
Reduction
6/4/2015
8
©2012 MFMER | slide-22
Stroke and Atrial Fibrillation
Alternative to Warfarin or NOACS
•Patients who could be
treated with
warfarin/NOACS
•Patients who choose not
to be treated with
warfarin/NOACS
•Contraindications to
warfarin/NOACS
©2012 MFMER | slide-23
