Watchman I: First Report of the 5-Year
PROTECT-AF and Extended PREVAIL
Results
Vivek Y. Reddy, MD
Helmsley Trust Professor of Medicine
Director, Cardiac Arrhythmia Service
The Mount Sinai Hospital
[email protected]
• Grant support/Consultant: Boston Scientific, Coherex
Medical, St Jude Medical
• I will be discussing the use of non-FDA approved
catheter-based devices
All faculty disclosures are available on
the CRF Events App and online at
www.crf.org/tct
PROTECT-AF: Overview
• Randomized FDA-IDE Trial
– Can the WATCHMAN device replace
Warfarin?
Non-Valvular AF
CHADs ≥ 1
• Efficacy Endpoint:
– Stroke
– CV death (& Unknown)
– Systemic embolism
• Safety Endpoint
Randomization (1:2)
Warfarin
Watchman
Anticoagulation Regimen
• Non-inferiority & Superiority
– Bayesian Sequential Design
– Analysis at 600 pt-yrs & every 150 pt-yrs
thereafter  1500 pt-yr
– Follow-up till 5 years
• Implant to 6 weeks
– Warfarin (INR 2-3) for 6 weeks
– Aspirin (81 – 325 mg)
• 6 weeks to 6 months
Follow-Up(75 mg)
– Clopidogrel
– Aspirin (81 – 325 mg)
• After 6 months
– Aspirin (81 – 325 mg)
Patient Enrollment
PROTECT
AF
PREVAIL
CAP
Registry
CAP2
Registry
Totals
Enrolled
800
461
566
579
2406
Roll-in
93
54
--
--
147
Randomized
707
407
--
--
1114
463 : 244
269 :138
566
579
1877: 382
2717
860
2022
332
5931
WATCHMAN :
warfarin (2:1)
Patient-years
Patient Enrollment
PROTECT
AF
PREVAIL
CAP
Registry
CAP2
Registry
Totals
Enrolled
800
461
566
579
2406
Roll-in
93
54
--
--
147
Randomized
707
407
--
--
1114
463 : 244
269 :138
566
579
1877: 382
2717
860
2022
332
5931
WATCHMAN :
warfarin (2:1)
Patient-years
Patient Demographics
Characteristic
Age, mean ± SD
PROTECT AF PREVAIL
N=707
N=407
CAP
N=566
CAP2
N=579
72.0 ± 8.9
74.3 ± 7.4
74.0 ± 8.3
75.3 ± 8.0
70.3%
70.0%
65.5%
61.0%
Asian
0.7%
0.5%
1.6%
0.7%
Black/Afr. American
1.6%
1.7%
1.9%
1.2%
Caucasian
91.5%
94.4%
91.9%
94.1%
Hispanic/Latino
5.7%
2.7%
3.5%
2.1%
Other
0.6%
0.7%
1.1%
1.0%
Sex (Male)
Ethnicity / Race
* Estimated
Majority of WATCHMAN
Patients are High Risk
Patients
CAP
PROTECT
AF
CAP
PREVAIL
PREVAIL
CAP2
CAP2
CHA2DS2-VASc Score
CHA2DS2-VASc
Score ≥2
96%
93%
96%
100%
100%
100%
Majority of WATCHMAN
Eligible for Anti-Coagulation
Patients
CAP
Anti-coagulation recommended
per ACC/AHA/HRSPREVAIL
Guidelines 2014
CAP2
CHA2DS2-VASc Score
96%
100%
100%
PREVAIL Met
Safety Primary Endpoint
WATCHMAN
(N=269)
Events
6
Patients (%)
2.23%
95% Credible Interval (CrI)
2.65%
Performance Goal (1-sided 95% CrI)
< 2.67%
Performance Goal
Event Rate (95% CrI)
Consistent Safety Profile Since
Second Half of PROTECT AF
2014
Patients
(%)
2013
PROTECT AF
N=232
N=231
1st Half
2nd Half
CAP
PREVAIL
CAP2
N=566
N=269
N=579
PROTECT AF: WATCHMAN Final
Primary Efficacy (2717 Pt Yrs)
Event Rate
(per 100 Pt-Yrs)
WATCHMAN Warfarin
Primary efficacy
2.2
3.7
1.5
2.2
Ischemic
1.3
1.1
Hemorrhagic
0.2
1.1
Systemic embolism
0.2
0.0
Death (CV/unexpl)
1.0
2.3
Stroke (all)
Rate Ratio
(95% CrI)
0.61
(0.42, 1.07)
0.68
(0.42, 1.37)
1.25
(0.72, 3.27)
0.15
(0.03, 0.49)
Posterior Probability
Non-inferiority Superiority
>99%
95.4%
>99%
83%
78%
15%
>99%
>99%
N/A
N/A
N/A
0.44
(0.26, 0.90)
>99%
99%
PROTECT AF: WATCHMAN Final
Primary Efficacy (2717 Pt Yrs)
Event Rate
(per 100 Pt-Yrs)
WATCHMAN Warfarin
Primary efficacy
2.2
3.7
1.5
2.2
Ischemic
1.3
1.1
Hemorrhagic
0.2
1.1
Systemic embolism
0.2
0.0
Death (CV/unexpl)
1.0
2.3
Stroke (all)
Rate Ratio
(95% CrI)
0.61
(0.42, 1.07)
0.68
(0.42, 1.37)
1.25
(0.72, 3.27)
0.15
(0.03, 0.49)
Posterior Probability
Non-inferiority Superiority
>99%
95.4%
>99%
83%
78%
15%
>99%
>99%
N/A
N/A
N/A
0.44
(0.26, 0.90)
>99%
99%
PROTECT AF: WATCHMAN Final
Primary Efficacy (2717 Pt Yrs)
Event Rate
(per 100 Pt-Yrs)
WATCHMAN Warfarin
Primary efficacy
2.2
3.7
1.5
2.2
Ischemic
1.3
1.1
Hemorrhagic
0.2
1.1
Systemic embolism
0.2
0.0
Death (CV/unexpl)
1.0
2.3
Stroke (all)
Rate Ratio
(95% CrI)
0.61
(0.42, 1.07)
0.68
(0.42, 1.37)
1.25
(0.72, 3.27)
0.15
(0.03, 0.49)
Posterior Probability
Non-inferiority Superiority
>99%
95.4%
>99%
83%
78%
15%
>99%
>99%
N/A
N/A
N/A
0.44
(0.26, 0.90)
>99%
99%
PROTECT AF:
All-Cause Mortality
All-Cause Mortality Posterior
Hazard Ratio
Probability
(95% CI)
(Superiority) p-value
0.69 (0.47, 1.03)
91.4%
0.063
Warfarin 244
233
222
216
204
192
176
161
153
143
93
WATCHMAN 463
403
389
381
372
360
352
341
334
324
243
PREVAIL: Efficacy Primary
Endpoint (2013 and 2014)
Posterior Probability
Non-inferiority
2013
93%
2014
93%
18-month Rate Ratio
Bayesian model results; Ad hoc analysis
PREVAIL Ad hoc Analysis: Second
Primary Endpoint (2013 vs 2014)
Posterior Probability
Non-inferiority
2013
97.6%
2014
89.2%
18-month Rate Difference
Bayesian model results
PREVAIL-only: New First
Events Since 2013 Panel
Endpoint Event
New First Events Since 2013 Panel
WATCHMAN
Warfarin
N=269
N=138
n
%
n
%
Primary Efficacy
10
3.7
5*
3.6
All Stroke
9
3.3
2
1.4
Ischemic
8
3.0
0
0
Hemorrhagic
1
0.4
2*
1.4
Systemic Embolism
0
0
0
0
Death (CV or Unexplained)
1
0.4
4*
2.9
* One patient had a hemorrhagic stroke followed by death. This was only counted as a single event for the combined
primary endpoint per the statistical analysis plan
* One patient had a hemorrhagic stroke followed by death. This was only counted as a single event for the combined primary endpoint per the
statistical analysis plan
PREVAIL-only: New First
Events Since 2013 Panel
Endpoint Event
New First Events Since 2013 Panel
WATCHMAN
Warfarin
N=269
N=138
n
%
n
%
Primary Efficacy
10
3.7
5*
3.6
All Stroke
9
3.3
2
1.4
Ischemic
8
3.0
0
0
Hemorrhagic
1
0.4
2*
1.4
Systemic Embolism
0
0
0
0
Death (CV or Unexplained)
1
0.4
4*
2.9
* One patient had a hemorrhagic stroke followed by death. This was only counted as a single event for the combined
primary endpoint per the statistical analysis plan
* One patient had a hemorrhagic stroke followed by death. This was only counted as a single event for the combined primary endpoint per the
statistical analysis plan
PREVAIL-only: Primary
Efficacy Rates
Endpoint Event
Composite Primary Efficacy
Total Endpoint Events
Event Rate (per 100 pt-yrs)
WATCHMAN
Warfarin
N=269
N=138
4.3
3.0
2.7
1.0
Ischemic
2.3
0.3
Hemorrhagic
0.4
0.7
0.2
0
Individual Components
All Stroke
Systemic Embolism
Death
or Unexplained)
* One patient
had a(CV
hemorrhagic
stroke followed by death. This was only1.4
counted as a single event for2.3
the combined
primary endpoint
* One patient had a hemorrhagic stroke followed by death. This was only counted as a single event for the combined primary endpoint per the
statistical analysis plan
PREVAIL: Warfarin Stroke
Rate Differs from Other Trials
Trial (Warfarin Arm)
Stroke / Embolism
Rate per 100 pt-yrs
Mean
CHADS2
PREVAIL
2.6
PROTECT AF
2.2
RE-LY1
2.1
ROCKET AF2
3.5
ARISTOTLE3
2.1
Rate per Patient-years
1. Connolly SJ. N Engl J Med (2009); 2. Patel MR. N Engl J Med (2011); 3. Granger CB. N Engl J Med (2011)
PREVAIL Ischemic Stroke Rate
Aligns with Expected Rate
CHA2DS2-VASc Score
Friberg. Eur Heart J (2012); NICE UK (2014)
PREVAIL Ischemic Stroke Rate
Aligns with Expected Rate
CHA2DS2-VASc Score
Friberg. Eur Heart J (2012); NICE UK (2014)
PREVAIL Ischemic Stroke Rate
Aligns with Expected Rate
CHA2DS2-VASc Score
Friberg. Eur Heart J (2012); NICE UK (2014)
PREVAIL Ischemic Stroke Rate
Aligns with Expected Rate
Warfarin
CHA2DS2-VASc Score
Friberg. Eur Heart J (2012); NICE UK (2014)
Now what?