LAA Syllabus

: Pdf Laa Syllabus LAA_Syllabus 6 2015 pdf

Open the PDF directly: View PDF .
Page Count: 46

Download
Open PDF In Browser	View PDF

6/16/2015

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
100

Age

40-64
65-69
70-74
75-79
80-84
85

80
60

%
40
20
0
0

2

4

6

Years after starting treatment
A.M.Gallagher J Thromb Haem 6:1500 (2008)

1

6/16/2015

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? Watchman
Barbs Engage
Wall
3. How safe is the Watchman LAA
implantation
procedure?
4. PROTECT AF/PREVAIL were randomized
160 µ PET
against Warfarin
… But now that we have
fabric
NOACs …
5. How cost-effective is LAAC?

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

Non-Valvular AF
Risk Factors
Randomization (1:2)

Warfarin
Watchman
Anticoagulation Regimen
• Implant to 6 weeks
– Warfarin
– Aspirin

• 6 weeks to 6 months
– Clopidogrel
Follow-Up
– Aspirin

• After 6 months
– Aspirin

2

6/16/2015

PROTECT AF
Superiority of Watchman over Warfarin
Primary Endpoint
[ Stroke / SE / CV Death ]

CV Death

Hemorrhagic Stroke: 85%↓↓
V.Reddy, H.Sievert, J.Halperin et al, JAMA, 312:1988 (2014)

All-Cause Mortality vs Warfarin
Is a 34% Mortality Benefit by LAAC Plausible?
All-Cause Mortality
LAAC vs Warfarin

NOACs vs Warfarin

Warfarin
Watchman

V.Reddy, H.Sievert, J.Halperin et al, JAMA, 312:1988 (2014)
Ruff et al. Lancet, 383:955 (2014)

PROTECT-AF & PREVAIL
Combined Analysis
Efficacy
All stroke or SE

HR

p-value

0.79

0.22

1.02

0.94

Ischemic stroke or SE

1.95

0.05

Hemorrhagic stroke

0.22

0.004

0.48

0.006

All-cause death

CV/unexplained death

0.73

0.07

Major bleed, all

1.00

0.98

Major bleeding, non procedure-related

0.51

0.002

Favors WATCHMAN 

0.01

0.1

 Favors warfarin

1

10

Hazard Ratio (95% CI)
D.Holmes et al, JACC (in press)

3

6/16/2015

PROTECT-AF & PREVAIL
Combined Analysis
Efficacy
All stroke or SE

HR

p-value

0.79

0.22

1.02

0.94

Ischemic stroke or SE

1.95

0.05

Hemorrhagic stroke

0.22

0.004

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

CV/unexplained death

Favors WATCHMAN 

0.01

0.1

 Favors warfarin

1

10

Hazard Ratio (95% CI)
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
CHA2DS2-VASc
Score ≥2
93%
PROTECT AF
96%
CAP
100%
PREVAIL
100%
CAP2

50%
50%
40%
40%
30%
Patients 30%
(%)
20%
20%
10%
10%
0%0%

00

11

33
44
22
CHA2DS2-VASc Score

5 5

6-9 6-9

4

6/16/2015

Modified HAS-BLED Score
> 90% Patients at Moderate/High Bleeding Risk

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

Study

* 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 (%)

12.0%
10.0%

9.9%

8.0%
6.0%

4.8%

4.0%

4.1%

4.1%

CAP

PREVAIL

CAP2

N=566

N=269

N=579

3.8%

2.0%
0.0%

PROTECT AF
N=232
1st Half

N=231
2nd Half

5

6/16/2015

Bleeding: A Safety Issue with OAC
Less Bleeding after 6-mo Post-Implantation
PROTECT-AF & PREVAIL Combined Analysis
100

90

WATCHMAN
Warfarin

Free of
Major 80
Bleeding
Event 70
(%)

HR = 0.29
p<0.001

60
Warfarin
+Aspirin

50

Warfarin
+Aspirin
78

0

Aspirin+
Clopidogrel

45 46

Aspirin

180 6

60

Time (days)

Time (months)

V.Reddy et al, FDA Panel Presentation, October 2014.

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
100%
90%

Anticoagulant Use in Patients with
NVAF and CHADS2 ≥ 2

40%

80%
70%

Total on Oral
Anticoagulation

60%
50%

Warfarin

40%

NOACs

30%
20%
10%
0%
2011 Q1 2011 Q2 2011 Q3 2011 Q4 2012 Q1 2012 Q2 2012 Q3 2012 Q4
n=25719

n=29194

n=31582

n=36490

n=67102

n=70667

n=70320

n=71396

Jani, et al. Results from the NCDR-Pinnacle Registry ACC -2014

6

6/16/2015

NOACs are Excellent Medications
But Not for Everyone…
RELY: Major Bleeding
w/ Anti-Platelet
7.0%
6.0%
5.0%
4.0%
3.0%
2.0%
1.0%
0.0%

NOAC
NOAC +
ASA/Clop

FDA Slide Deck. Dabigatran FDA Review from Panel Meeting 2010

Preventing Stroke in Non-Valvular AF
Imputed Benefit of Different Strategies (vs Control)
*

Stroke Reduction
(vs Placebo)

*
0%
-10%
-20%
-30%
-40%
-50%
-60%
-70%
-80%
-90%

*

*

* 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?

7

6/16/2015

Economic Analysis: Budget Impact
Watchman vs Dabigatran vs Warfarin

S.L.Amarosi et al, Europace, 16:1131 (2014)

Amplatzer Cardiac Plug Registry
Efficacy
6%

5.62%

5%
-59%
4%

Effectiveness in Bleeding
Reduction vs Estimated

Estimated
based on
CHA2DS2-VASc
ScoreAmplatzer
Observed rate
in study

3%

Annual Bleeding Risk

Annual Stroke Risk

Effectiveness in Stroke Reduction
vs Estimated

6%
5.34%

5%
-61%
4%

Estimated
based on
HAS-BLED
Score
Observed rate
in study

3%

2.30%

2.08%

2%

2%

1%

1%

0%

0%

Total Patients

Total Patient Years

CHA2DS2-VASc Score

1001

1349

4.43

Total Patients

Total Patient Years

HAS-BLED
Score

1001

1349

3.12

Estimated Stroke Rate per
CHA2DS2-VASc

Actual Annual Stroke Rate
(N strokes + TIA)

Estimated Bleeding Rate per
HAS-BLED

Actual Annual Bleeding Rate
(N major bleeds)

5.62%

2.30% (31)

5.34%

2.08% (28)

Tzikas A et al, EuroIntervention (in press)

Final Thoughts
LA Appendage Closure & Stroke Prevention
•

~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]

8

6/16/2015

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 nonpharmacologic alternative to warfarin, taking into
account the safety and effectiveness of the device
compared to warfarin.

Watchman: FDA Labeling
Device Patient Selection Considerations
Rationale for seeking an
alternative to warfarin:
 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

Factors to consider for
Watchman implantation:
 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

9

08/06/2015

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 Atrial
Appendage
Left Atrium

Lariat LAA closure animation

1

08/06/2015

The Next Generation LARIAT + Device

Lariat +
snare width increased from

40 mm → 45 mm

Platinum-Iridium
“L” Marker

“L” Marker

Improved torque-ability of catheter due to
stainless steel wire braid on catheter shaft

Lariat LAA ligation closure may result in
a permanent transmural lesion
Pre CT

45-day Post CT

No LAA

LAA

Lariat LAA ligation closure may result in
a permanent transmural lesion

LAA
LAA

Suture

Endo

LA

1 cm

LAA
LA

LA

Endo

Bartus et al Circ Arrhythmia 2014; 7: 764-767

2

08/06/2015

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

3

08/06/2015

4

6/11/2015

VuMedi Webinar

12min

Endocardial Devices

F
CHMAN
CVRF
cational
entific)
1

soo
YoungKim
Kyeong
June
Kim,
Sun Kim,
ang Kim,
wan Lee,
oung
Cheol
g Yu

Sameer Gafoor, Horst Sievert, Patrick Böhm,
Ilona Hofmann, Laura Vaskelyte, Stefan Bertog
CardioVascular Center Frankfurt - CVC
Frankfurt, Germany

Update
AC and Lecturer: Saibal
Kar
ical
nce
of
in the
New

Lecturer: Horst
Sievert

rements
Lecturer:
uccessful
Matthew Price
Program

CHMAN
Lecturer: Teguh
Center
Santoso
ence

ssion

-

Indications and
indications

CardioVascular Center Frankfurt CVC

Atrial fibrillation is one of the most important stroke
causes, especially in the elderly
Framingham Study, Wolf, 1991
40

%

35
30
25
20
15
10
5
0

50-59

60-69

70-79

80-89

Age

1

6/11/2015

Anticoagulation in AF
Randomised Trials
–66%*

14
12

–71%*

–86%*

AFASAK

BAATAF

–69%*

–52%

–79%*

SPAF-I

CAFA

SPINAF

10
8
6
4
2
0

Control

Warfarin

EAFT

*p<0.05

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

2

6/11/2015

Lone Atrial Fibrillation
Only about 1/3 of all eligible
patients are taking Coumadin

100%
80%
60%

not on Coumadin
on Coumadin

40%
20%
0%
<65

65-74

75-79

>80

Stafford and Singer, Arch Int Med, 1996

CardioVascular Center Frankfurt CVC

Lone Atrial Fibrillation
100%
80%
60%
not on Coumadin
on Coumadin

40%
20%
0%

<65

65-74

75-79

>80

Stafford and Singer, Arch Int Med, 1996

CardioVascular Center Frankfurt CVC

CHA2DS2VASc
• CHA2DS2VASc, developed by Lip et al, is a refinement of the older CHADS 2
Score which includes additional stroke risk factors and puts greater emphasis on
age as a risk factor1
Points

18%

Congestive heart failure

1

15%

H

Hypertension

1

13%

A2

Age ≥75 years

2

D

Diabetes Mellitus

1

S2

Previous stroke or TIA

2

V

Vascular disease

1

A

Age 65-74 years

1

3%

Sc

Sex (female gender)

1

0%

Risk of Stroke

Condition/Risk Factor
C

15.2%

9.8% 9.6%

10%
6.7%

8%
5%

European Society of Cardiology Guidelines 2012
CHA2DS2-VASc Score

Annual Risk of Stroke

1.3%

2.2%

3.2%

6.7%

4.0%

0.0%

0

1

2

3

4

5

6

7

8

9

CHA2DS2VASc Score

Treatment

0 or 1 and female

none

≥1

Coumadin or NOAC
1. Lip GY et al, Chest 2010;137(2):263-72

CardioVascular Center Frankfurt CVC

3

6/11/2015

Is there another option
to reduce this?

CardioVascular Center Frankfurt CVC

Where do thrombi form?
N

Appendage

Percent

LA Body

Percent

TEE

Setting

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

201

90.5

21

9.5

Total

Reference

2018

Total Thrombus

222

Blackshear and Odell, Ann Thoracic Surgery 1996

CardioVascular Center Frankfurt CVC

Who among
us has not
seen this?
Or at least
been tested
on it?

4

6/11/2015

Stroke Prophylaxis: LAA Closure

Blackshear and Odell, Ann Thoracic Surgery 1996

Where is the
evidence?

Trials to know…
•
•
•
•

PROTECT AF
CAP
PREVAIL
ASAP

CardioVascular Center Frankfurt CVC

5

6/11/2015

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

CardioVascular Center Frankfurt CVC

6

6/11/2015

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

CardioVascular Center Frankfurt CVC

7

6/11/2015

Primary safety endpoint
Watchman is non-inferior to warfarin

CardioVascular Center Frankfurt CVC

Ischemic stroke

CV Mortality

RR 1.26, p=NS

RR 0.40 p=0.005

All-cause mortality

RR 0.66 p=0.04

CardioVascular Center Frankfurt CVC

Safety endpoint

CardioVascular Center Frankfurt CVC

8

6/11/2015

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

CardioVascular Center Frankfurt CVC

9

6/11/2015

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

CardioVascular Center Frankfurt CVC

Performance – Learning Curve Effect
PROTECT-AF vs. CAP
Serious Pericardial Effusion Within 7 Days

Procedure/Device Related Safety Adverse
Event Within 7 Days

10

10

8
10
5,5

5

3,7

Incidence %

Incidence %

15

6,3

6

4

3,7
2,2

2

0

0
PROTECT AF Early PROTECT AF Late

CAP

PROTECT AF Early PROTECT AF Late

CAP

Procedure Related Stroke

With increased operator experience,
the procedure related adverse
events and serious pericardial
effusions were reduced significantly.
Peri-procedural strokes were
eliminated

5
Incidence %

4
3

2
1

1,1

0,7
0

0
PROTECT AF Early PROTECT AF Late

CAP

Reddy, Circulation 2011

10

6/11/2015

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
CardioVascular Center Frankfurt CVC

11

6/11/2015

PREVAIL

CardioVascular Center Frankfurt CVC

PREVAIL patients were
different

CardioVascular Center Frankfurt CVC

Implant success
improved

CardioVascular Center Frankfurt CVC

12

6/11/2015

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

CardioVascular Center Frankfurt CVC

13

6/11/2015

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

CardioVascular Center Frankfurt CVC

14

6/11/2015

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?

Camm EHJ 2012

ESC 2012 Update Afib Guidelines

CardioVascular Center Frankfurt CVC

15

6/11/2015

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

CardioVascular Center Frankfurt CVC

16

6/11/2015

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

CardioVascular Center Frankfurt CVC

17

No
complication
s

articipated
other FIM
als

6/11/2015

Meier, Sievert et al. Eurointerv 2014

CardioVascular Center Frankfurt CVC

PLAATO™ Occluder
ePTFE
Membrane

Hooks
LAA

LA

Nitinol
frame

First LAA closure Aug 30, 2001

• Procedure time 85 min
• Coumadin off since 2001
• Had his 84th birthday in Jan
2013
• Zero bleeding
• Zero embolic events

18

eris
h

6/11/2015

PLAATO
• Technical success rate
94%
• Periprocedural MAE
5%
• No device related complications
beyond 30 days
• Stroke risk reduction 65%
• FU up to 11 yrs

CardioVascular Center Frankfurt CVC

LAA Closure
Endocardial

Epicardial

• PLAATO
• Watchman
• ACP  Amulet
• Coherex
• Sideris Patch
• Occlutech
• pfm Medical
• Lifetech
• Cardia

• SentreHeart
• AEGIS
• AtriCure
• Medtronic

Watchman Occluder
•
•
•
•

Nitinol
PET membrane
Hooks
21, 24, 27, 30,
33 mm

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)

CE mark

19

6/11/2015

Watchman Implantation
• LAA diameter in TEE
19 mm

Watchman Implantation
Maximum
Implant
measured diameter
LAA ostium (mm)
(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

PROTECT AF:
Primary Efficacy Endpoint:
Stroke, Death, Systemic Embolization
Watchman is superior to warfarin (p<0.05)
Hazard Ratio 0.6

CardioVascular Center Frankfurt CVC

20

6/11/2015

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

Amplatzer Cardiac Plug

•
•
•
•

Lobe diameter 16-30mm
Lobe length 6.5mm
Disk diameter 20-36mm
9, 10 or 13F sheath

CardioVascular Center Frankfurt CVC

21

6/11/2015

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

CardioVascular Center Frankfurt CVC

Amplatzer Cardiac Plug
Post-Market EU Registry
Patients Consented
N = 206

Consented Screen Failures
N=2

Patients Enrolled
N = 204

Failed to Implant N = 7
(Device withdrawn in 5)

Device Implanted
N = 197

Technical success 96.6%

1 month follow up
N = 191
6 month follow up
N = 183

Device/Procedure Related
Safety Events
≤7 Days

>7 days

Post Procedure

Post Procedure

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%)

Total

* The stroke/TIA is reference to device or procedure related strokes as adjudicated by the AE
Review Committee.

N=204

22

6/11/2015

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

CardioVascular Center Frankfurt CVC

23

6/11/2015

Coherex WaveCrest

20
points
of
anchori
ng

• Retractable anchors
.
• ePTFE occluder material
is occlusive and nonthrombogenic
• Distal contrast injection
• to assess stability
• to assess occlusion
• 3 sizes (22, 27, 32mm)
CE mark Aug 2013

The Coherex WAVECREST I Trial
Gen 1.3
enrolled
patients
n = 63
implant
successful
n=61

implant
unsuccessful
n=2
lost to follow
up n=1

per protocol
population
n=60

The Coherex WAVECREST I Trial
Primary Efficacy Endpoint

45 day closure2

intent to treat
(n = 63)

per protocol1
(n=60)

58 (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

24

6/11/2015

The Coherex WAVECREST I Trial
Primary Safety Endpoint
MAEs through 45 Days
Enrolled population
Device embolization
Pericardial effusion
Stroke or TIA
Device associated thrombus

N = 63
0
0
0
0

25

6/4/2015

Future of LAA Closure
David R. Holmes, Jr., M.D.
Mayo Clinic, Rochester
VuMedi Webinar
June 2015

©2012 MFMER | slide-1

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.

©2012 MFMER | slide-2

Parekh A, Ezekowitz M et al: Circ 114:e513, 2006

Disappearing LAA Thrombus Resulting in Stroke

©2014 MFMER | 3392826-3

1

6/4/2015

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-4

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-5

Location of Thrombi in Left Atrium
91% in LAA
Total
Hart: Stroke, 1994
Leurig: JACC, 1994
Klein: Circ, 1994
Manning: Circ, 1994
Klein: Int J Card Imag, 1993
Tsai: JFMA, 1990
Aberg: Acta Med Scan, 1969
Manning: Circ, 1994
Stoddard: JACC, 1995

0

20

40

60

80

100

Location frequency (%)
Left atrial appendage

Left atrium

Blackshear et al: Ann Thoracic Surg 61, 1996
©2012 MFMER | slide-6

2

6/4/2015

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 | 3393308-7

CHA2DS2-VASc Refines Stroke Risk
Determination in AF Patients
CHA2DS2-VASc Risk Criteria

One Year Stroke Risk
25

Risk Factor

Score

Prior stroke or TIA

2

20

Age ≥75
Age 65-74

2
1

15

Hypertension

1

10

Diabetes mellitus

1

5

Heart failure

1

Vascular disease

1

Female sex

1

0

0

1

2

3

4

5

6 7-9

CHADS2-VASc Score
Mason PK: Am J Medicine, 2012
©2014 MFMER | 3392826-8

HAS-BLED Stratifies Bleeding Risk
on Warfarin
HAS-BLED
Condition
Hypertension
Abnormal liver and
renal function
(1 point each)
Stroke
Bleeding
Labile INR
Age >65
Drugs or alcohol
(1 point each)

Incidence of Major Bleeding
Events (% per year)
Points
1

15

1 or 2

10

1
1
1
1

5

1 or 2

0

0

1

2

3

5

4

HAS-BLED Score
Roldan V: Chest, 2013
©2014 MFMER | 3392826-9

3

6/4/2015

Bleeding

Stroke

©2012 MFMER | slide-10

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
©2014 MFMER | 3393308-11

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
©2012 MFMER | slide-12

4

6/4/2015

LAA Closure for Stroke Prevention in
Non-Valvular AF

Bergmann MW et al: EuroIntervention 2014;10:497-504
©2012 MFMER | slide-13

PROTECT AF: Long-Term Efficacy Results
(2,621 Patient-Years of Follow-Up)
Event rate
(per 100 pt-yr)

Posterior
probabilities

WATCHMAN
n=463

Control
n=244

Rate ratio
(95% Crl)

Noninferiority 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

0.999

0.2

1.1

0.15 (0.03, 0.49)

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-14

PROTECT AF: Long-Term Results
(2,621 Patient-Years of Follow-Up)
Event rate
(per 100 pt-yr)

Posterior
probabilities

WATCHMAN
n=463

Control
n=244

Rate ratio
(95% Crl)

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

0.2

0.0

n/a

n/a

n/a

1.0

2.4

0.40 (0.23, 0.82)

>0.999

0.995

Systemic
Embolism
Death (CV &
unexplained)

Noninferiority Superiority

PAF

CAP

PREVAIL

©2012 MFMER | slide-15

5

6/4/2015

“I got a bad feeling about this, Harriet.”
©2012 MFMER | slide-16

Safety Events:
PROTECT AF, CAP, PREVAIL
12
9.9

Patients (%)

10
8
6

4.8

4

4.1

4.2

2
PROTECT
AF

CAP
Registry

0

1st half

2nd half

CAP

PREVAIL

n=232

n=231

n=566

n=269

PREVAIL

PROTECT AF
©2012 MFMER | slide-17

PROTECT AF/PREVAIL Meta-Analysis:
WATCHMAN Comparable to Warfarin
Efficacy
All stroke or SE

HR

P

0.79

0.22

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

0.48

0.006

All-cause death

0.73

0.07

Major bleed, all

1.00

0.98

0.51

0.002

CV/unexplained death

Major bleeding, non procedure-related
Favors WATCHMAN 

0.01

0.1

 Favors warfarin

1

10

Hazard Ratio (95% CI)
©2014 MFMER | 3392826-18

6

6/4/2015

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-19

Aspirin and Plavix® Registry (ASAP)
The ASAP registry is a nonrandomized feasibility study
designed to evaluate if the
WATCHMAN® Device is a safe
and effective treatment for
people unable to take warfarin

• Patients may be treated with
aspirin and/or clopidogrel; this
treatment paradigm has a
higher stroke risk than warfarin

10
Stroke risk (%)

• AF patients who are
contraindicated or intolerant of
warfarin have few options for
thromboembolic prophylaxis

12

Annual risk of stroke with
secondary prevention of aspirin
or warfarin

8

Aspirin
Warfarin

11%

7%

6
4

4%
3%

2
0
PRIOR TIA

PRIOR STROKE

The WATCHMAN Device is not approved for patients contraindicated to OACs
©2012 MFMER | slide-20

Results
Expected and Observed Stroke Rates (per 100 patient-years)
8.0

7.3%

7.0
6.0
5.0

5.0%

77%
Reduction

Expected,
if Clopidogrel was used
throughout follow-up

4.0
3.0
2.0

Expected,
based on CHADS2 score

1.7%

Observed rate in ASAP

1.0
0.0

Observed rate of ischemic stroke represents a 77%
reduction from the expected event rate
©2012 MFMER | slide-21

7

6/4/2015

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-22

©2012 MFMER | slide-23

8



---

Source Exif Data:

File Type                       : PDF
File Type Extension             : pdf
MIME Type                       : application/pdf
PDF Version                     : 1.4
Linearized                      : No
Modify Date                     : 2015:06:16 10:37:39-04:00
Creator                         : PDFMerge! (http://www.pdfmerge.com)
Create Date                     : 2015:06:16 10:37:39-04:00
Producer                        : iText® 5.5.2 ©2000-2014 iText Group NV (ONLINE PDF SERVICES; licensed version)
Page Count                      : 46

EXIF Metadata provided by EXIF.tools