MetaAnalysis and Implications David R Holmes Jr MD Mayo Clinic Rochester TCT 2014 Washington DC September 2014 Presenter Disclosure Information David R Holmes Jr MD Watchman II PROTECT AFPREVAIL ID: 663287
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Slide1
Watchman II: PROTECT AF/PREVAILMeta-Analysis and Implications
David R. Holmes, Jr., M.D.Mayo Clinic, Rochester
TCT 2014
Washington, D.C.
September 2014Slide2
Presenter Disclosure Information
David R. Holmes, Jr., M.D.
“
Watchman II: PROTECT AF/PREVAIL
Meta-Analysis and Implications”
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.Slide3
Choose your
ruts carefully;
You’ll be in them
for the next
40 milesSlide4
BackgroundPREVAIL results demonstrated improved safety of LAAC implants with both new and experienced operatorsPROTECT AF 4 year data demonstrated superior efficacy of Watchman Implantation
5 year results confirm superiorityHowever, PREVAIL missed a statistical endpoint goal making the efficacy data difficult to interpretSlide5
All Serious Complications7 Day Serious Procedure/Device Related
Composite
of vascular complications includes cardiac perforation, pericardial effusion with tamponade, ischemic stroke, device embolization, and other vascular
complications
1
n=39
n=23
n=12
p = 0.004
No procedure-related deaths
in randomized patients in any
trials
1
Includes observed PE not necessitating intervention, AV fistula, major bleeding requiring transfusion, pseudoaneurysm, hematoma and groin bleeding
PROTECT AF and CAP: Reddy, VY et al. Circulation. 2011;123:417-424.
PREVAIL: Holmes, DR et al.
JACC
2014;
In PressSlide6
PROTECT-AF:
Primary Efficacy Endpoint (2013 vs. 2014)
Ra
t
e
Ra
t
io
Posterior Probability
Non-inferiority
Superiority
December 2013 Panel (2621 Patient-years)
Efficacy
0.61
>99%
95%
S
t
r
o
k
e
(
a
ll
)
0.68
>99%
83%
S
y
s
te
m
i
c
e
m
bo
li
s
m
N/A
N/A
N/A
Death
(
C
V
/u
n
e
x
p
l
a
i
n
ed
)
0.44
>99%
99%
October 2014 Panel (2717 Patient-years)
Efficacy
0.60
>99%
95%
Stroke (all)
0.68
>99%
83%
S
y
s
te
m
i
c
e
m
bo
li
s
m
N/A
N/A
N/A
Death
(
C
V
/u
n
e
x
p
l
a
i
n
ed
)
0.40
>99%
>99%Slide7
PREVAIL TrialPrimary Endpoints
One-sided 95% upper CI bound for success
2.0%
2.5%
3.0%
Percent of patients experiencing an event
2.2%
2.618%
2.67%
Early Safety
95%
upper CI bound for non-inferiority
0.5
1.0
1.5
18-month Rate Ratio
2.0
1.07
0.57
1.89
1.75
Primary Efficacy
95% upper CI bound for non-inferiority
-0.01
0
0.01
18-month Rate Difference
0.02
0.0053
-0.02
0.03
-0.03
-0.0190
0.0273
0.0275
Late Ischemic Efficacy
Acute (7-day) occurrence of death, ischemic stroke, systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
Endpoint Success: 6 events in device group = 2.2% (6/269)
Comparison
of composite of stroke, systemic embolism, and cardiovascular/unexplained
death
Similar 18-month event rates in both
device and control
groups =
0.064 vs. 0.063
Comparison
of ischemic stroke or systemic embolism occurring >7 days post randomization
Endpoint success in the presence of an over performing control groupSlide8
PREVAIL TrialPrimary Endpoints (Updated Final Analysis)
Holmes, DR et al. JACC 2014;
In Press
Comparison
of composite of stroke, systemic embolism, and cardiovascular/unexplained
death
Wide credible intervals
Posterior Probability for Non-inferiority = 93%
1.75
18-month Rate Ratio
95%
upper CI bound for non-inferiority
Dec 2013
Jun 2014
Primary
Efficacy
Comparison
of ischemic stroke or systemic embolism occurring >7 days post randomization
Wide credible intervals
Posterior Probability for Non-inferiority = 89.2%
18-month Rate
Difference
95%
upper CI bound for non-inferiority
0.0275
Late Ischemic Efficacy
Dec 2013
Jun 2014Slide9
PREVAIL Control (Warfarin) Group Performance
In spite of the high average CHADS2 score of 2.6 in the control group, the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studiesPREVAIL control group rate = 1.0 (95% CI 0.3, 3.1)
Wide confidence bounds due to small number of patients with 18-months of
follow-up
TrialControl (Warfarin) Group Stroke, Systemic Embolism Rate
(
Per 100 PY)
PROTECT AF
1
1.6
RE-LY (Dabigatran)
2
1.7
ARISTOTLE (Apixaban)
3
1.6
ROCKET AF (Rivaroxaban)
4
2.2
PREVAIL
5
1.0
1
Ischemic stroke rate
from
Holmes et al.
Lancet
2009; 374:534-42
2
Connolly et al.
N
Engl
J Med
2009; 361:1139-51
3
Granger et al.
N
Engl
J Med
2011; 365:981-92
4
Patel et al.
N
Engl
J Med
2011; 365:883-91
5
Holmes, DR et al. JACC 2014; In PressSlide10
PurposeTo evaluate the totality of randomized data of WATCHMAN versus warfarin forComposite efficacy
StrokeDeathBleedingSlide11
MethodsPatient level data was pooled across the 2 randomized trials: PROTECT
AF and PREVAIL. Baseline demographics and risk factors compared across trials using:Student's t-test (for continuous variables)
Fisher's
exact test (for categorical
variables)Endpoints were compared across treatment groups using a Cox proportional hazards model stratified by trial. Slide12
Efficacy
0.22
0.79
Patient-Level Meta-Analysis
EfficacyHazard Ratio (95% CI)P-value
Favors WATCHMAN
Favors warfarin
HRSlide13
All stroke or SE
0.94
1.02
Ischemic stroke or SE
0.051.95
Hemorrhagic stroke
0.004
0.22
Patient-Level Meta-Analysis
Stroke
Hazard Ratio (95% CI)
P-value
Favors WATCHMAN
Favors warfarin
HRSlide14
Major bleed
0.98
1.00
Major bleed beyond 7 days
0.0020.51
Patient-Level Meta-Analysis
Major Bleeding
Hazard Ratio (95% CI)
P-value
Favors WATCHMAN
Favors warfarin
HRSlide15
Characteristic
PROTECT AF
N=463
PREVAIL
N=269
P value
Age, years
71.7 ± 8.8 (463)
(46.0, 95.0)
74.0
±
7.4
(
269)
(
50.0, 94.0
)
<0.001
Gender (Male)
326/463 (70.4%)
182/269
(
67.7%)
0.252
CHADS
2
Score (Continuous)
2.2 ±
1.2
(1.0, 6.0)
2.6
±
1.0
(
1.0, 6.0
)
<0.001
CHADS
2
Risk Factors
CHF
124/463 (26.8%)
63/269
(
23.4%)
Hypertension
415/463 (89.6%)
238/269
(
88.5%)
Age ≥ 75
190/463 (41.0%)
140/269
(
52.0%)
Diabetes
113/463 (24.4%)
91/269
(
33.8%)
Stroke/TIA
82/463 (17.7%)
74/269
(
27.5%)
Demographics
Device Patients
PROTECT AF and CAP: Reddy, VY et al. Circulation. 2011;123:417-424.
PREVAIL: Holmes, DR et al.
JACC
2014;
In Press
Most notable differences:
Age, Diabetes, and Prior Stroke/TIASlide16
PROTECT AF “PREVAIL like” Patients vs PREVAILFirst Primary Endpoint
WATCHMAN Groups
Warfarin GroupsSlide17
PROTECT AF “PREVAIL like” Patients vs PREVAILSecond Primary Endpoint
WATCHMAN Groups
Warfarin GroupsSlide18
All-cause death
0.07
0.73
Cardiovascular /
unexplained death0.0060.48
Patient-Level Meta-Analysis
Mortality
Hazard Ratio (95% CI)
P-value
Favors WATCHMAN
Favors warfarin
HRSlide19
SummaryOutcomes
with WATCHMAN were comparable to warfarin for primary efficacy (HR=0.79) Although there were more ischemic strokes in the warfarin arm (HR=1.95), WATCHMAN had significant reduction in hemorrhagic stroke (HR=0.22)There was a significant reduction in CV mortality for WATCHMAN versus warfarin (HR=0.48)Slide20
ConclusionsThe WATCHMAN device is an alternative to oral anticoagulation therapy for thromboembolic prevention in patients with non valvular atrial fibrillation Slide21Slide22
What is Democracy of Numbers?
A Meta-AnalysisSlide23
Choose your
ruts carefully;
You’ll be in them
for the next
40 milesSlide24
ConclusionsAdditional analyses would be helpful to compare Device performance against historical warfarin performance
Imputed placeboThe WATCHMAN device is an alternative to oral anticoagulation therapy for thromboembolic prevention in patients with non valvular atrial fibrillation Slide25Slide26
Stroke and Atrial FibrillationAlternative to Warfarin or NOACS
Patients who could be treated with warfarin/NOACSPatients who choose not to be treated with warfarin/NOACSContraindications to warfarin/NOACSSlide27Slide28
New medicines and new methods of cure always work miracles for awhile
William Heberden
1710-1801Slide29
BackgroundPREVAIL results demonstrated improved safety of LAAC implants with both new and experienced operatorsPROTECT AF 4 year data demonstrated superior efficacy
5 year results confirmPREVAIL missed endpoint makes the efficacy data difficult to interpretSlide30
PREVAIL: Prospective Randomized Evaluation of the Watchman Left Atrial
Appendage Closure Device in Patients With Atrial Fibrillation Versus Long-Term Warfarin TherapyDavid
Holmes
1
, Saibal Kar2, Matthew Price3, Brian Whisenant4, Horst Sievert5, Shephal K Doshi6, Kenneth Huber7, Vivek Y. Reddy81Mayo Clinic, MN; 2Cedars Sinai Medical Center, CA; 3
Scripps
Clinic, La Jolla
, CA;
4
Intermountain
Medical Center
, UT;
5
Sankt
Katharinen
, Frankfurt; 6Pacific
Heart Institute, CA; 7St Luke’s Hospital, MO; 8
Mount Sinai School of Medicine, NYSlide31
Device
Control
Posterior Probabilities
Observed rate
(events per 100 pt-yrs)
(95% CrI)
Observed rate
(events per 100 pt-yrs)
(95% CrI)
Rate Ratio
Intervention/Control
(95% CrI)
Non-inferiority
Superiority
Primary
Efficacy
3.0
(2.1, 4.3)
4.3
(2.6,
5.9
)
0.71
(0.44, 1.30)
>0.99
0.88
Primary Safety
5.5
( 4.2, 7.1)
3.6
(2.2, 5.3)
1.53
(0.95, 2.70)
N/A
N/A
PROTECT AF:
Primary Efficacy and Safety
Results
at 1,500 Patient
Years
Primary Efficacy
Safety
Reddy, VY et al. Circulation. 2013;127:720-729.Slide32
Study Objective
Confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
Design
Prospective, randomized (2:1) WATCHMAN™ LAA Closure Technology to warfarin
Inclusion of new centers and new operators to show enhancements to the training program are effective to confirm late PROTECT-AF and CAP safety Primary EndpointsEarly Safety: Acute (7-day) occurrence of death, ischemic stroke, systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular interventionPrimary Efficacy: Comparison of composite of stroke, systemic embolism, and cardiovascular/unexplained deathLate Ischemic Efficacy: Comparison of ischemic stroke or systemic embolism occurring >7 days post randomization Patient
Population
n = 407 randomized
patients
Mean Age = 74.3 ± 7.3
Mean CHADS
2
=2.6 ± 1.0
Number of Sites
41 in the United States (18 new sites)
50 implanters
(24 new operators)
Enrollment
Nov 2010 - Jun 2012PREVAIL TrialBackground
Holmes, DR et al. JACC 2014; In PressSlide33
PREVAIL Enrollment
Total Enrolled461
Roll-In Patients
54
Implant Attempt54Device Implanted51
Unable to Implant
3
Randomized
Patients
407
WATCHMAN
(Device)
269
Warfarin
(Control)
138
Implant Attempt
265
No Implant Attempt
4
Device Implanted
252
Unable to Implant
13Slide34
Characteristic
PROTECT AF
N=463
CAP
N=566PREVAIL
N=269
P value
Age, years
71.7 ± 8.8 (463)
(46.0, 95.0)
74.0 ± 8.3 (566)
(44.0, 94.0)
74.0
±
7.4
(
269)
(
50.0, 94.0
)
<0.001
Gender (Male)
326/463 (70.4%)
371/566 (65.5%)
182/269
(
67.7%)
0.252
CHADS
2
Score (Continuous)
2.2 ±
1.2
(1.0, 6.0)
2.5 ± 1.2
(1.0, 6.0)
2.6
±
1.0
(
1.0, 6.0
)
<0.001
CHADS
2
Risk Factors
CHF
124/463 (26.8%)
108/566 (19.1%)
63/269
(
23.4%)
Hypertension
415/463 (89.6%)
503/566 (88.9%)
238/269
(
88.5%)
Age ≥ 75
190/463 (41.0%)
293/566 (51.8%)
140/269
(
52.0%)
Diabetes
113/463 (24.4%)
141/566 (24.9%)
91/269
(
33.8%)
Stroke/TIA
82/463 (17.7%)
172/566 (30.4%)
74/269
(
27.5%)
Demographics
Device Patients
PROTECT AF and CAP: Reddy, VY et al. Circulation. 2011;123:417-424.
PREVAIL: Holmes, DR et al.
JACC
2014;
In Press
Most notable differences:
Age, Diabetes, and Prior Stroke/TIASlide35
Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
p = 0.01
Study
45-day
12-month
PROTECT AF
86.6%
93.2%
PREVAIL
92.2%
99.3%
Implant success defined as deployment and release of the device into the left atrial appendage
Warfarin Cessation
PREVAIL Implant Success
No difference between new
and experienced operators
Experienced Operators
n=26, 96.2%
New Operators
n=24, 93.2%
p = 0.282
PROTECT AF and CAP: Reddy, VY et al. Circulation. 2011;123:417-424.
PREVAIL: Holmes, DR et al.
JACC
2014;
In PressSlide36
All Serious Complications7 Day Serious Procedure/Device Related
Composite
of vascular complications includes cardiac perforation, pericardial effusion with tamponade, ischemic stroke, device embolization, and other vascular
complications
1
n=39
n=23
n=12
p = 0.004
No procedure-related deaths reported in any of the trials
1
Includes observed PE not necessitating intervention, AV fistula, major bleeding requiring transfusion, pseudoaneurysm, hematoma and groin bleeding
PROTECT AF and CAP: Reddy, VY et al. Circulation. 2011;123:417-424.
PREVAIL: Holmes, DR et al.
JACC
2014;
In PressSlide37
PREVAIL
Pericardial Effusions
n=7
n=1
n=1
n=11
n=7
n=4
p = 0.027
P = 0.36
PROTECT AF and CAP: Reddy, VY et al. Circulation. 2011;123:417-424.
PREVAIL: Holmes, DR et al.
JACC
2014;
In PressSlide38
PREVAIL
Peri-procedural Stroke
n=5
n=0
n=1PROTECT AF and CAP: Reddy, VY et al. Circulation. 2011;123:417-424.PREVAIL: Holmes, DR et al.
JACC
2014;
In Press
p = 0.007
Procedure/Device Related StrokesSlide39
PREVAIL ConclusionsBased On Final Pre-specified Analysis
From January 2013Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators 2 of 3 primary endpoints were met even in the presence of an over performing control groupResults of the PREVAIL trial add to the wealth of previously published data on
WATCHMANSlide40
Transcatheter Heart Valve Review
20 mm
23 mm
26 mm
29 mmBovine pericardium,
ThermaFix
tissue treatment
Cobalt-chromium alloy
16-19
18-22
21-25
24-28
273-345
338-430
430-546
540-680
18.6-21.0
20.7-23.4
23.4-26.4
26.2-29.4
21.0
24.5
27.0
31.0
15.5
18.0
20.0
22.5
5.5
6.5
7.0
8.5
7.9
9.3
10.2
11.6
5.2
6.6
7.0
8.1
SAPIEN 3 THV
Tissue
Frame
2D TEE diameter sealing zone (mm)
3D area sealing zone (mm
2
)
3D area-derived diameter (mm)
Crimped height (mm)
Expanded height (mm)
Foreshortening (mm)
Inner skirt height (mm)
Outer skirt height (mm)
SAPIEN XT THV
23 mm
26 mm
29 mm
Bovine pericardium,
ThermaFix
tissue treatment
Cobalt-chromium alloy
18-22
21-25
24-27
–
–
–
–
–
–
17.0
20.0
22.0
14.0
17.0
19.0
3.0
3.0
3.0
6.7
8.7
11.6Slide41
Transcatheter Heart Valve Review
SAPIEN XT THV
23 mm
26 mm
29 mmTissue
Bovine pericardium,
ThermaFix
tissue treatment
Frame
Cobalt-chromium alloy
2D TEE diameter sealing zone (mm)
18-22
21-25
24-27
3D area sealing
zone
–
–
–
3D area-derived diameter
–
–
–
Crimped height (mm)
17.0
20.0
22.0
Expanded height (mm)
14.0
17.0
19.0
Foreshortening (mm)
3.0
3.0
3.0
Inner skirt height (mm)
6.7
8.7
11.6Slide42
Transcatheter Heart Valve Review
SAPIEN 3 THV
20 mm
23 mm
26 mm29 mm
Tissue
Bovine pericardium,
ThermaFix
tissue treatment
Frame
Cobalt-chromium alloy
2D TEE diameter sealing zone (mm)
16-19
18-22
21-25
24-28
3D area sealing zone (mm
2
)
273-345
338-430
430-546
540-680
3D area-derived diameter (mm)
18.6-21.0
20.7-23.4
23.4-26.4
26.2-29.4
Crimped height (mm)
21.0
24.5
27.0
31.0
Expanded height (mm)
15.5
18.0
20.0
22.5
Foreshortening (mm)
5.5
6.5
7.0
8.5
Inner skirt height (mm)
7.9
9.3
10.2
11.6
Outer skirt height (mm)
5.2
6.6
7.0
8.1Slide43
Questions & DiscussionSlide44
Holmes, David
Valve Review – 3365707
This is the side title color
Type first bulleted point here
Type first subpoint hereThis is the highlight
color
ma 8/8/2014
Color Theme
%
A
B
C
D
E
F
X-Y Axis
Highlight
Footnote/subdue
Notes
Bold & Shadow all Text
Black borders on bar graphs
Line graphs: No shadow on lines
Row
Color
No.
%
1
Red
12.3
47
2
Yellow
459.2
26
3
Green
56.7
98