Vivek Y Reddy MD Helmsley Trust Professor of Medicine Director Cardiac Arrhythmia Service The Mount Sinai Hospital vivekreddymountsinaiorg Grant supportConsultant Boston Scientific ID: 599575
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Watchman I: First Report of the 5-Year PROTECT-AF and Extended PREVAIL Results
Vivek Y. Reddy, MDHelmsley Trust Professor of MedicineDirector, Cardiac Arrhythmia ServiceThe Mount Sinai Hospitalvivek.reddy@mountsinai.org
Grant support/Consultant
: Boston Scientific,
Coherex
Medical, St Jude Medical
I will be discussing the use of non-FDA approved catheter-based devicesSlide2
All faculty disclosures are available on the CRF Events App
and online at www.crf.org/tctSlide3
PROTECT-AF: Overview
Randomized FDA-IDE TrialCan the WATCHMAN device replace Warfarin?Efficacy Endpoint:StrokeCV death (& Unknown)Systemic embolismSafety EndpointNon-inferiority & SuperiorityBayesian Sequential DesignAnalysis at 600 pt-yrs & every 150 pt-yrs thereafter
1500 pt-yr
Follow-up till 5 years
Follow-Up
Non-Valvular AF
CHADs ≥ 1
Randomization (1:2)
Warfarin
Watchman
Anticoagulation Regimen
Implant to 6 weeks
Warfarin (INR 2-3) for 6 weeks
Aspirin (81 – 325 mg)
6 weeks to 6 months
Clopidogrel (75 mg)
Aspirin (81 – 325 mg)
After 6 months
Aspirin (81 – 325 mg)Slide4
PROTECT AF
PREVAILCAPRegistry
CAP2
Registry
Totals
Enrolled
800
461566579
2406
Roll-in
93
54
--
--147Randomized707407----
1114WATCHMAN : warfarin (2:1)463 : 244269 :1385665791877: 382
Patient-years271786020223325931Patient Enrollment Slide5
PROTECT AF
PREVAILCAPRegistry
CAP2
Registry
Totals
Enrolled
800
461566579
2406
Roll-in
93
54
--
--147Randomized707407----
1114WATCHMAN : warfarin (2:1)463 : 244269 :1385665791877: 382
Patient-years271786020223325931Patient Enrollment Slide6
Characteristic
PROTECT AFN=707
PREVAIL
N=407
CAP
N=566
CAP2
N=579Age, mean ± SD72.0 ±
8.9
74.3
±
7.4
74.0 ± 8.3
75.3 ± 8.0Sex (Male)70.3%70.0%
65.5%61.0%Ethnicity / Race
Asian0.7%0.5%1.6%0.7%
Black/Afr. American1.6%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%Other0.6%0.7%1.1%1.0%
Patient Demographics
* EstimatedSlide7
CAP
96%
PREVAIL
100%
CAP2
100%
Majority of WATCHMAN
Patients are High Risk
Patients
CHA
2
DS
2
-VASc Score
CAP
96%
PREVAIL
100%
CAP2
100%
CHA
2
DS
2
-VASc Score ≥2
PROTECT AF
93%Slide8
CAP
96%
PREVAIL
100%
CAP2
100%
Majority of WATCHMAN
Eligible for Anti-Coagulation
Patients
CHA
2
DS
2
-VASc Score
Anti-coagulation recommended
per ACC/AHA/HRS Guidelines 2014Slide9
PREVAIL Met Safety Primary Endpoint
WATCHMAN(N=269)Events6Patients (%)
2.23%
95% Credible Interval (CrI)
2.65%
Performance Goal (1-sided 95%
CrI
)< 2.67%
Event Rate (95% CrI)
Performance GoalSlide10
Consistent Safety Profile Since Second Half of PROTECT AF
Patients(%)
PROTECT AF
2013
2014
1
st
Half
2
nd
Half
N=232
N=231
N=566
N=269N=579CAPPREVAILCAP2Slide11
Event Rate
(per 100 Pt-Yrs)
Rate Ratio
(95% CrI)
Posterior Probability
WATCHMAN
Warfarin
Non-inferiority
Superiority
Primary efficacy
2.2
3.7
0.61
(0.42, 1.07)
>99%
95.4%
Stroke (all)
1.5
2.2
0.68
(0.42, 1.37)
>99%
83%
Ischemic
1.3
1.1
1.25
(0.72, 3.27)
78%
15%
Hemorrhagic
0.2
1.1
0.15
(0.03, 0.49)
>99%
>99%
Systemic embolism
0.2
0.0
N/A
N/A
N/A
Death (CV/unexpl)
1.0
2.3
0.44
(0.26, 0.90)
>99%
99%
PROTECT AF: WATCHMAN Final Primary Efficacy (2717 Pt Yrs)Slide12
Event Rate
(per 100 Pt-Yrs)
Rate Ratio
(95% CrI)
Posterior Probability
WATCHMAN
Warfarin
Non-inferiority
Superiority
Primary efficacy
2.2
3.7
0.61
(0.42, 1.07)
>99%
95.4%
Stroke (all)
1.5
2.2
0.68
(0.42, 1.37)
>99%
83%
Ischemic
1.3
1.1
1.25
(0.72, 3.27)
78%
15%
Hemorrhagic
0.2
1.1
0.15
(0.03, 0.49)
>99%
>99%
Systemic embolism
0.2
0.0
N/A
N/A
N/A
Death (CV/unexpl)
1.0
2.3
0.44
(0.26, 0.90)
>99%
99%
PROTECT AF: WATCHMAN Final Primary Efficacy (2717 Pt Yrs)Slide13
Event Rate
(per 100 Pt-Yrs)
Rate Ratio
(95% CrI)
Posterior Probability
WATCHMAN
Warfarin
Non-inferiority
Superiority
Primary efficacy
2.2
3.7
0.61
(0.42, 1.07)
>99%
95.4%
Stroke (all)
1.5
2.2
0.68
(0.42, 1.37)
>99%
83%
Ischemic
1.3
1.1
1.25
(0.72, 3.27)
78%
15%
Hemorrhagic
0.2
1.1
0.15
(0.03, 0.49)
>99%
>99%
Systemic embolism
0.2
0.0
N/A
N/A
N/A
Death (CV/unexpl)
1.0
2.3
0.44
(0.26, 0.90)
>99%
99%
PROTECT AF: WATCHMAN Final Primary Efficacy (2717 Pt Yrs)Slide14
PROTECT AF:
All-Cause Mortality All-Cause MortalityHazard Ratio(95% CI)
Posterior
Probability
(Superiority)
p-value
0.69 (0.47, 1.03)
91.4%0.063244
233
222
216
204
192
17616115314393
463403389381372
360352341334324243
WarfarinWATCHMANSlide15
Posterior
Probability2013
93%
2014
93%
PREVAIL: Efficacy Primary Endpoint (2013 and 2014)
18-month Rate Ratio
Non-inferiority
Bayesian model results; Ad hoc analysisSlide16
Posterior
Probability2013
97.6%
2014
89.2%
PREVAIL Ad hoc Analysis: Second Primary Endpoint (2013 vs 2014)
18-month Rate Difference
Non-inferiority
Bayesian model resultsSlide17
Endpoint Event
New First Events Since 2013 PanelWATCHMAN N=269
Warfarin
N=138
n
%
n
%
Primary Efficacy10
3.7
5*
3.6
All Stroke
93.321.4Ischemic83.0
00Hemorrhagic10.42*1.4
Systemic Embolism0000Death (CV or Unexplained)
10.44*2.9PREVAIL-only: New First Events Since 2013 Panel
* 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 planSlide18
Endpoint Event
New First Events Since 2013 PanelWATCHMAN N=269
Warfarin
N=138
n
%
n
%
Primary Efficacy10
3.7
5*
3.6
All Stroke
93.321.4Ischemic83.0
00Hemorrhagic10.42*1.4
Systemic Embolism0000Death (CV or Unexplained)
10.44*2.9PREVAIL-only: New First Events Since 2013 Panel
* 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 planSlide19
Endpoint Event
Total Endpoint EventsEvent Rate (per 100 pt-yrs)WATCHMAN
N=269
Warfarin
N=138
Composite Primary Efficacy
4.3
3.0Individual Components
All Stroke
2.7
1.0
Ischemic
2.3
0.3Hemorrhagic0.40.7
Systemic Embolism0.20Death (CV or Unexplained)1.42.3PREVAIL-only: Primary Efficacy Rates
* One patient had a hemorrhagic stroke followed by death. This was only counted as a single event for 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 planSlide20
PREVAIL: Warfarin Stroke Rate Differs from Other Trials
Rate per Patient-years
Trial (Warfarin Arm)
Stroke / Embolism
Rate per 100 pt-yrs
Mean CHADS
2
PREVAIL
2.6
PROTECT AF
2.2
RE-LY
1
2.1ROCKET AF
23.5ARISTOTLE3
2.11. Connolly SJ. N Engl J Med (2009)
; 2. Patel MR. N Engl J Med (2011); 3. Granger CB. N Engl J Med (2011)Slide21
PREVAIL Ischemic Stroke Rate Aligns with Expected Rate
PAF
2013: 1.4
2014: 1.3
PREVAIL
2013: 1.9
2014: 2.3
CHADS VASC
PAF: 3.5PREVAIL: 4.0
Friberg.
Eur Heart J (2012); NICE UK (2014)
CHA
2
DS2-VASc ScoreSlide22
PREVAIL Ischemic Stroke Rate Aligns with Expected Rate
PAF
2013: 1.4
2014: 1.3
PREVAIL
2013: 1.9
2014: 2.3
CHADS VASC
PAF: 3.5PREVAIL: 4.0
Friberg.
Eur Heart J (2012); NICE UK (2014)
CHA
2
DS2-VASc ScoreSlide23
PREVAIL Ischemic Stroke Rate Aligns with Expected Rate
PAF
2013: 1.4
2014: 1.3
PREVAIL
2013: 1.9
2014: 2.3
CHADS VASC
PAF: 3.5PREVAIL: 4.0
Friberg.
Eur Heart J (2012); NICE UK (2014)
CHA
2
DS2-VASc ScoreSlide24
PREVAIL Ischemic Stroke Rate Aligns with Expected Rate
PAF
2013: 1.4
2014: 1.3
PREVAIL
2013: 1.9
2014: 2.3
CHADS VASC
PAF: 3.5PREVAIL: 4.0
Friberg.
Eur Heart J (2012); NICE UK (2014)
CHA
2
DS2-VASc Score
WarfarinSlide25
Now what?Slide26