1. 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
Grant support/Consultant: Boston Scientific, Coherex Medical, St Jude Medical
I will be discussing the use of non-FDA approved catheter-based devices 1

2. All faculty disclosures are available on the CRF Events App and online at www.crf.org/tct

3. PROTECT-AF: Overview Randomized FDA-IDE Trial Efficacy Endpoint:
Can the WATCHMAN device replace Warfarin?
Efficacy Endpoint:
Stroke
CV death (& Unknown)
Systemic embolism
Safety Endpoint
Non-inferiority & Superiority
Bayesian Sequential Design
Analysis 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)
After 6 months

4. Patient Enrollment PROTECT AF PREVAIL CAP Registry CAP2 Totals
Enrolled
800
461
566
579
2406
Roll-in 93 54 --
147
Randomized
707
407
1114
WATCHMAN : warfarin (2:1)
463 : 244
269 :138
1877: 382
Patient-years
2717
860
2022
332
5931
A total of 2406 patients have been enrolled in the WATCHMAN clinical program: 800 in PROTECT, 461 in PREVAIL, 566 in CAP and 579 in CAP2.
PROTECT and PREVAIL allowed for roll-in patients, to familiarize new operators with the procedure. We performed sensitivity analyses including these patients and presented them at both previous panels.
CAP and CAP2 were registries and did not have roll-ins, as all operators were experienced PROTECT or PREVAIL implanters…
Overall, we have 1877 patients implanted with WATCHMAN, and almost 6,000 patient-years of total follow-up in these 4 trials.
[PAUSE]
Looking at the demographics of these patients…

5. Patient Enrollment PROTECT AF PREVAIL CAP Registry CAP2 Totals
Enrolled
800
461
566
579
2406
Roll-in 93 54 --
147
Randomized
707
407
1114
WATCHMAN : warfarin (2:1)
463 : 244
269 :138
1877: 382
Patient-years
2717
860
2022
332
5931
A total of 2406 patients have been enrolled in the WATCHMAN clinical program: 800 in PROTECT, 461 in PREVAIL, 566 in CAP and 579 in CAP2.
PROTECT and PREVAIL allowed for roll-in patients, to familiarize new operators with the procedure. We performed sensitivity analyses including these patients and presented them at both previous panels.
CAP and CAP2 were registries and did not have roll-ins, as all operators were experienced PROTECT or PREVAIL implanters…
Overall, we have 1877 patients implanted with WATCHMAN, and almost 6,000 patient-years of total follow-up in these 4 trials.
[PAUSE]
Looking at the demographics of these patients…

6. Patient Demographics Characteristic PROTECT AF N=707 PREVAIL N=407 CAP
Age, mean ± SD
72.0 ± 8.9
74.3 ± 7.4
74.0 ± 8.3
75.3 ± 8.0
Sex (Male)
70.3%
70.0%
65.5%
61.0%
Ethnicity / Race
Asian
0.7%
0.5%
1.6%
Black/Afr. American
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%
1.1%
1.0%
These trials enrolled a relatively elderly population, with a mean age of 72 to 75.
[PAUSE]
Two thirds of the patients in these trials were male and they were primarily Caucasian.
[PAUSE] 
Looking at the risk factors for these patients…
* Estimated

7. Majority of WATCHMAN Patients are High Risk
CHA2DS2-VASc Score ≥2
PROTECT AF
93%
CAP
96%
PREVAIL
100%
CAP2
CAP
96%
PREVAIL
100%
CAP2
Patients
…93% of patients in PROTECT had a CHADS VASc score of 2 OR MORE.
[PAUSE]
Thus, most PROTECT patients are considered high risk according to the more contemporary and more sensitive indicator of stroke risk.
[CLICK]
Similarly, 96% of the CAP patients and ALL PREVAIL and CAP2 patients had scores of 2 or more.
CHA2DS2-VASc Score

8. Majority of WATCHMAN Eligible for Anti-Coagulation
Anti-coagulation recommended
per ACC/AHA/HRS Guidelines 2014
CAP
96%
PREVAIL
100%
CAP2
Patients
…93% of patients in PROTECT had a CHADS VASc score of 2 OR MORE.
[PAUSE]
Thus, most PROTECT patients are considered high risk according to the more contemporary and more sensitive indicator of stroke risk.
[CLICK]
Similarly, 96% of the CAP patients and ALL PREVAIL and CAP2 patients had scores of 2 or more.
CHA2DS2-VASc Score

9. 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
With an event rate of 2.23%, an upper credible interval of 2.65% and a performance goal of 2.67…PREVAIL DID meet the safety primary endpoint
[PAUSE]
Event Rate (95% CrI)

10. Consistent Safety Profile Since Second Half of PROTECT AF
Patients
(%)
PROTECT AF
2013
2014
1st Half
2nd Half
N=232
N=231
N=566
N=269
N=579
CAP
PREVAIL
CAP2
At the December 2013 Panel, we demonstrated an improved procedure safety profile over the course of the clinical studies. Within Paf itself, the safety event rate decreased by over 50% from the 1st half to the 2nd half of the study. 
And this lower safety event rate…around 4%...was maintained throughout the subsequent trials…Cap and Prevail.
[PAUSE]
We can now show you the NEW safety data from the 579 patients enrolled in the Cap2 registry…again, a low complication rate…only 3.8%.
Note that this safety event rate is similar to that seen by even ESTABLISHED cardiovascular interventions such as AF ablation. In the worldwide AF survey, published in 2010, the major complication rate was 4.5%...and this included serious complications such as cardiac tamponade, stroke or tia, pulmonary vein stenosis, and serious vascular complications such as pseudoaneurysm or A-V Fistula.
Together, these results emphasize that Watchman demonstrates a favorable safety profile.
Moving on to efficacy…

11. PROTECT AF: WATCHMAN Final Primary Efficacy (2717 Pt Yrs)
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
0.68
(0.42, 1.37)
83%
Ischemic
1.3
1.1
1.25
(0.72, 3.27)
78%
15%
Hemorrhagic
0.2
0.15
(0.03, 0.49)
Systemic embolism
0.0
N/A
Death (CV/unexpl)
1.0
2.3
0.44
(0.26, 0.90)
99%
The composite primary efficacy is superior after 5 years of follow up, with Watchman demonstrating a 39% reduction in events over warfarin with a posterior probability for superiority of 95.4%,
As we look at the individual components of the primary efficacy endpoint…
[CLICK]
…we see a 32% relative reduction in the rate of all strokes, with continued non-inferiority to warfarin.
We also see a numerically, but not statistically significant, higher rate of ischemic strokes in the Watchman arm. This is driven primarily by procedure-related strokes -- AND –
is offset by an 85% reduction in hemorrhagic stroke, the kind of stroke known to result in the greatest patient disability and death.
Systemic embolism remains consistently low .
And Cardiovascular or unexplained death is significantly reduced by 56% at the 5 year time point.
[PAUSE]
From a clinical perspective, cardiovascular death is the most IMPACTFUL component of the primary endpoint…

12. PROTECT AF: WATCHMAN Final Primary Efficacy (2717 Pt Yrs)
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
0.68
(0.42, 1.37)
83%
Ischemic
1.3
1.1
1.25
(0.72, 3.27)
78%
15%
Hemorrhagic
0.2
0.15
(0.03, 0.49)
Systemic embolism
0.0
N/A
Death (CV/unexpl)
1.0
2.3
0.44
(0.26, 0.90)
99%
The composite primary efficacy is superior after 5 years of follow up, with Watchman demonstrating a 39% reduction in events over warfarin with a posterior probability for superiority of 95.4%,
As we look at the individual components of the primary efficacy endpoint…
[CLICK]
…we see a 32% relative reduction in the rate of all strokes, with continued non-inferiority to warfarin.
We also see a numerically, but not statistically significant, higher rate of ischemic strokes in the Watchman arm. This is driven primarily by procedure-related strokes -- AND –
is offset by an 85% reduction in hemorrhagic stroke, the kind of stroke known to result in the greatest patient disability and death.
Systemic embolism remains consistently low .
And Cardiovascular or unexplained death is significantly reduced by 56% at the 5 year time point.
[PAUSE]
From a clinical perspective, cardiovascular death is the most IMPACTFUL component of the primary endpoint…

13. PROTECT AF: WATCHMAN Final Primary Efficacy (2717 Pt Yrs)
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
0.68
(0.42, 1.37)
83%
Ischemic
1.3
1.1
1.25
(0.72, 3.27)
78%
15%
Hemorrhagic
0.2
0.15
(0.03, 0.49)
Systemic embolism
0.0
N/A
Death (CV/unexpl)
1.0
2.3
0.44
(0.26, 0.90)
99%
The composite primary efficacy is superior after 5 years of follow up, with Watchman demonstrating a 39% reduction in events over warfarin with a posterior probability for superiority of 95.4%,
As we look at the individual components of the primary efficacy endpoint…
[CLICK]
…we see a 32% relative reduction in the rate of all strokes, with continued non-inferiority to warfarin.
We also see a numerically, but not statistically significant, higher rate of ischemic strokes in the Watchman arm. This is driven primarily by procedure-related strokes -- AND –
is offset by an 85% reduction in hemorrhagic stroke, the kind of stroke known to result in the greatest patient disability and death.
Systemic embolism remains consistently low .
And Cardiovascular or unexplained death is significantly reduced by 56% at the 5 year time point.
[PAUSE]
From a clinical perspective, cardiovascular death is the most IMPACTFUL component of the primary endpoint…

14. PROTECT AF: All-Cause Mortality
All-Cause Mortality Hazard Ratio (95% CI)
Posterior
Probability
(Superiority)
p-value
0.69 (0.47, 1.03)
91.4%
0.063
As you can see from these Kaplan Meier curves, for all-cause mortality, the hazard ratio is 0.69 in favor of Watchman, with a posterior probability of superiority of 91.4% and p-value of
[PAUSE]
Minimally, these data demonstrate that over the long-term, the Watchman group does NOT experience an increase in mortality, in this, the largest randomized study of LAA closure.
Let’s turn our attention to the smaller, second randomized study…PREVAIL…
Warfarin
244
233
222
216
204
192
176
161
153
143 93
463
403
389
381
372
360
352
341
334
324
243
WATCHMAN

15. PREVAIL: Efficacy Primary Endpoint (2013 and 2014)
Posterior Probability
2013
93%
2014
Non-inferiority
Recall that in December, the primary efficacy endpoint was not met.
[PAUSE]
We re-ran the endpoint calculation for this endpoint with the updated dataset.
The endpoint is still not met, with a rate ratio of 1.21 and again, wide credible intervals. The posterior probability for non-inferiority is the same as it was in 2013…93%.
18-month Rate Ratio
Bayesian model results; Ad hoc analysis

16. PREVAIL Ad hoc Analysis: Second Primary Endpoint (2013 vs 2014)
Posterior Probability
2013
97.6%
2014
89.2%
Non-inferiority
Unlike Protect, recall that Prevail had a second primary endpoint focusing on ISCHEMIC-only strokes and systemic embolisms after the peri-procedural period.
This endpoint was barely met in 2013, again with very wide credible intervals….the rate difference was , with a posterior probability for non-inferiority of 97.6%.
Turning to today’s analysis, the wide credible intervals around the rate difference remain, but now cross the boundary for non-inferiority. That is, this endpoint is NOT met, with a posterior probability for non-inferiority of 89.2%. 
[PAUSE]
So…… what do these results tell us?
18-month Rate Difference
Bayesian model results

17. PREVAIL-only: New First Events Since 2013 Panel
Endpoint Event
New First Events Since 2013 Panel
WATCHMAN
N=269
Warfarin
N=138 n %
Primary Efficacy 10
3.7 5*
3.6
All Stroke 9
3.3 2
1.4
Ischemic 8
3.0
Hemorrhagic 1
0.4 2*
Systemic Embolism
Death (CV or Unexplained) 4*
2.9
…And what you will see is 10 NEW primary efficacy events in the Watchman arm and 5 NEW events in the warfarin arm.
Remember, since patients were randomized 2-to-1 Watchman to warfarin, these events occurred in roughly the same percentage of patients…3.7% of Watchman patients and 3.6% of warfarin patients.
While the numbers are extremely small, a review of the individual components shows:
[CLICK]
Across both arms, there have been 8 new ischemic strokes,
3 hemorrhagic strokes,
no systemic embolism,
and 5 CV deaths.
Comparing between groups, there are more new ISCHEMIC strokes in the device arm…this is offset by FOUR times as many HEMORRHAGIC strokes and almost EIGHT times more deaths in the warfarin arm.
[PAUSE]
* 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

18. PREVAIL-only: New First Events Since 2013 Panel
Endpoint Event
New First Events Since 2013 Panel
WATCHMAN
N=269
Warfarin
N=138 n %
Primary Efficacy 10
3.7 5*
3.6
All Stroke 9
3.3 2
1.4
Ischemic 8
3.0
Hemorrhagic 1
0.4 2*
Systemic Embolism
Death (CV or Unexplained) 4*
2.9
…And what you will see is 10 NEW primary efficacy events in the Watchman arm and 5 NEW events in the warfarin arm.
Remember, since patients were randomized 2-to-1 Watchman to warfarin, these events occurred in roughly the same percentage of patients…3.7% of Watchman patients and 3.6% of warfarin patients.
While the numbers are extremely small, a review of the individual components shows:
[CLICK]
Across both arms, there have been 8 new ischemic strokes,
3 hemorrhagic strokes,
no systemic embolism,
and 5 CV deaths.
Comparing between groups, there are more new ISCHEMIC strokes in the device arm…this is offset by FOUR times as many HEMORRHAGIC strokes and almost EIGHT times more deaths in the warfarin arm.
[PAUSE]
* 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

19. PREVAIL-only: Primary Efficacy Rates
Endpoint Event
Total Endpoint Events
Event Rate (per 100 pt-yrs)
WATCHMAN
N=269
Warfarin
N=138
Composite Primary Efficacy
4.3
3.0
Individual Components
All Stroke
2.7
1.0
Ischemic
2.3
0.3
Hemorrhagic
0.4
0.7
Systemic Embolism
0.2
Death (CV or Unexplained)
1.4
This table combines the new events to those we saw in Note that unlike the previous slide, these are annualized rates. Just like with Protect…
[CLICK]
[PAUSE]
We see more ischemic strokes in the Watchman arm…but again this is balanced by more hemorrhagic strokes and deaths in the warfarin arm.
In order to interpret these data, we need to examine two aspects of these results. FIRST, you may notice the lack of ischemic strokes in the warfarin arm. There was only ONE ischemic stroke in the warfarin arm after 2.2 years of follow up. If we compare this rate to other contemporary trials…
* 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 plan

20. 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
Here, we are looking at stroke plus embolism rates in the Warfarin arms of various trials. We see that the observed rate in Prevail of only 1 event per 100 patient years, is quite unlike the higher rates observed in the warfarin arms of Protect, Rely, Rocket Af, and Aristotle. And this occurred despite a higher Chads score in Prevail than all of these trials except Rocket.
As evident from the wide confidence intervals, the most likely explanation is the small sample size of Prevail…that is, merely chance. Of course we can’t rule out the possibility of other confounding reasons for this discrepancy, such as difficulty in classification of stroke type. For example, ischemic strokes could have transformed and thus been adjudicated as hemorrhagic stroke or CV deaths.
[PAUSE]
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)

21. 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: 3.5
PREVAIL: 4.0
In this slide, I will show that the ischemic stroke rates in the Watchman arms of the randomized trials are in line with expected rates based on risk scores.
This graph plots the ischemic stroke risk as events per 100 patient years, seen on the y-axis, as a function of the ChadsVasc score on the x-axis.
The DOTTED black line, on top, shows the expected stroke rate for untreated patients.
The SOLID black line, on the bottom, shows the expected reduced stroke rate for patients treated with Warfarin as a function of the risk score. These expected rates were obtained from the 2012 Swedish AF cohort study of over 180,000 patients, and the 2014 patient decision aid document from the UK National Institute for Health and Care Excellence.
[CLICK]
The ischemic stroke rates in the device arms of the 2 randomized trials are shown in the green and blue triangles for the 2013 dataset. Note that these rates are consistent with the solid line --- that is, the SAME reduction in ischemic stroke as one sees with warfarin after adjusting for Chads Vasc score.
And in 2014, both trials remain in line with expected rates.
[PAUSE]
So in these last several slides, I have shown that the device performance was consistent in Prevail from 2013 to 2014…
That the device performance in Prevail was consistent with the other, larger Watchman trials.
And, in this slide, the device performance in Prevail aligns with the expected ischemic stroke reductions as compared with warfarin.
CHA2DS2-VASc Score
Friberg. Eur Heart J (2012); NICE UK (2014)

22. 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: 3.5
PREVAIL: 4.0
In this slide, I will show that the ischemic stroke rates in the Watchman arms of the randomized trials are in line with expected rates based on risk scores.
This graph plots the ischemic stroke risk as events per 100 patient years, seen on the y-axis, as a function of the ChadsVasc score on the x-axis.
The DOTTED black line, on top, shows the expected stroke rate for untreated patients.
The SOLID black line, on the bottom, shows the expected reduced stroke rate for patients treated with Warfarin as a function of the risk score. These expected rates were obtained from the 2012 Swedish AF cohort study of over 180,000 patients, and the 2014 patient decision aid document from the UK National Institute for Health and Care Excellence.
[CLICK]
The ischemic stroke rates in the device arms of the 2 randomized trials are shown in the green and blue triangles for the 2013 dataset. Note that these rates are consistent with the solid line --- that is, the SAME reduction in ischemic stroke as one sees with warfarin after adjusting for Chads Vasc score.
And in 2014, both trials remain in line with expected rates.
[PAUSE]
So in these last several slides, I have shown that the device performance was consistent in Prevail from 2013 to 2014…
That the device performance in Prevail was consistent with the other, larger Watchman trials.
And, in this slide, the device performance in Prevail aligns with the expected ischemic stroke reductions as compared with warfarin.
CHA2DS2-VASc Score
Friberg. Eur Heart J (2012); NICE UK (2014)

23. 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: 3.5
PREVAIL: 4.0
In this slide, I will show that the ischemic stroke rates in the Watchman arms of the randomized trials are in line with expected rates based on risk scores.
This graph plots the ischemic stroke risk as events per 100 patient years, seen on the y-axis, as a function of the ChadsVasc score on the x-axis.
The DOTTED black line, on top, shows the expected stroke rate for untreated patients.
The SOLID black line, on the bottom, shows the expected reduced stroke rate for patients treated with Warfarin as a function of the risk score. These expected rates were obtained from the 2012 Swedish AF cohort study of over 180,000 patients, and the 2014 patient decision aid document from the UK National Institute for Health and Care Excellence.
[CLICK]
The ischemic stroke rates in the device arms of the 2 randomized trials are shown in the green and blue triangles for the 2013 dataset. Note that these rates are consistent with the solid line --- that is, the SAME reduction in ischemic stroke as one sees with warfarin after adjusting for Chads Vasc score.
And in 2014, both trials remain in line with expected rates.
[PAUSE]
So in these last several slides, I have shown that the device performance was consistent in Prevail from 2013 to 2014…
That the device performance in Prevail was consistent with the other, larger Watchman trials.
And, in this slide, the device performance in Prevail aligns with the expected ischemic stroke reductions as compared with warfarin.
CHA2DS2-VASc Score
Friberg. Eur Heart J (2012); NICE UK (2014)

24. 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: 3.5
PREVAIL: 4.0
In this slide, I will show that the ischemic stroke rates in the Watchman arms of the randomized trials are in line with expected rates based on risk scores.
This graph plots the ischemic stroke risk as events per 100 patient years, seen on the y-axis, as a function of the ChadsVasc score on the x-axis.
The DOTTED black line, on top, shows the expected stroke rate for untreated patients.
The SOLID black line, on the bottom, shows the expected reduced stroke rate for patients treated with Warfarin as a function of the risk score. These expected rates were obtained from the 2012 Swedish AF cohort study of over 180,000 patients, and the 2014 patient decision aid document from the UK National Institute for Health and Care Excellence.
[CLICK]
The ischemic stroke rates in the device arms of the 2 randomized trials are shown in the green and blue triangles for the 2013 dataset. Note that these rates are consistent with the solid line --- that is, the SAME reduction in ischemic stroke as one sees with warfarin after adjusting for Chads Vasc score.
And in 2014, both trials remain in line with expected rates.
[PAUSE]
So in these last several slides, I have shown that the device performance was consistent in Prevail from 2013 to 2014…
That the device performance in Prevail was consistent with the other, larger Watchman trials.
And, in this slide, the device performance in Prevail aligns with the expected ischemic stroke reductions as compared with warfarin.
Warfarin
CHA2DS2-VASc Score
Friberg. Eur Heart J (2012); NICE UK (2014)

25. Now what?