1. Keynote Lecture The 5 Best Trials from 2012 that will Impact My Practice
Gregg W. Stone, MD
Columbia University Medical Center
NewYork-Presbyterian Hospital
Cardiovascular Research Foundation

2. Consulting: Boston Scientific, Volcano
Gregg W. Stone, MD
Consulting:
Boston Scientific, Volcano

3. Top 6 Trials of 2012 SYNTAX 5-Year Outcomes FREEDOM FAME 2 WOEST
PARTNER 2-Year
RESPECT

5. Mohr FW et al. Lancet 2013

6. Mohr FW et al. Lancet 2013

7. Mohr FW et al. Lancet 2013

8. Mohr FW et al. Lancet 2013

9. 1 Endpoint: Death, Stroke, or MI
FREEDOM: 1900 pts with diabetes MVD randomized to SES/PES vs. CABG
1 Endpoint: Death, Stroke, or MI 30
PCI/DES
CABG
26.6% 20
18.7%
Death, Stroke, MI, %
13.0% 10
11.9%
P = 0.005 1 2 3 4 5 6
Years
PCI/DES
953
848
788
625
416
219 40
CABG
943
814
758
613
422
221 44
Farkouh ME et al. NEJM 2012 8

10. Death, Stroke, MI by Syntax Score
SYNTAX Score  22 (N=669)
SYNTAX Score (N=844) 40 40
PCI/DES (N=329)
CABG (N=340)
PCI/DES (N=438)
CABG (N=406) 30 30
27.2%
23.2%
Death, MI, Stroke (%) 20
Death, MI, Stroke (%) 20
17.2%
17.7% 10 10
0.0
1.0
2.0
3.0
4.0
5.0
0.0
1.0
2.0
3.0
4.0
5.0
Years
Years
SYNTAX Score 33 (N=374)
Years
0.0
1.0
2.0
3.0
4.0
5.0
PCI/DES (N=182)
CABG (N=192) 40 30 20 10
30.6%
PCI/DES
Pint=0.58
22.8%
Death, MI, Stroke (%)
CABG
Farkouh ME et al. NEJM 2012 9

11. FAME 2: Flow Chart 73% 27% N = 1220 Registry Randomized Trial
11% Silent ischemia
21% Class I
45% Class II
16% Class III
7% Class IV, stabilized
Stable CAD patients scheduled for PCI
N = 1220
FFR in all target lesions
Randomized Trial
Registry
At least 1 stenosis
with FFR ≤ 0.80 (n=888)
When all FFR > 0.80
(n=332)
*Of 1,632 planned
* 332/1220 pts (27.2%) in whom PCI was planned had no physiologically significant lesion and were treated with MT only in the registry
Randomization 1:1
PCI + MT MT MT
73%
27%
50% randomly
assigned to FU
Follow-up: 1 month, 6 months, 1, 2, 3, 4, and 5 years (mean ~7 mos)
De Bruyne B et al. NEJM 2012:on-line 10

12. De Bruyne B et al. NEJM 2012:on-line
FAME 2: Primary Endpoint All-cause death, MI or urgent revascularization
PCI+MT vs. MT: HR 0.32 ( ); p<0.001 30
PCI+MT vs. Registry: HR 1.29 ( ); p=0.61 25
MT vs. Registry: HR 4.32 ( ); p<0.001 20
urgent revasc (%)
Death, MI, or 15 10 5 1 2 3 4 5 6 7 8 9 10 11 12
Months
No. at risk MT
441
414
370
322
283
253
220
192
162
127
100 70 37
PCI+MT
447
414
388
351
308
277
243
212
175
155
117 92 53
Registry
166
156
145
133
117
106 93 74 64 52 41 25 13
De Bruyne B et al. NEJM 2012:on-line 11

13. FAME 1: Primary Endpoint
1005 pts with MVD undergoing PCI with DES were randomized to FFR-guided vs. angio-guided intervention
FFR-guided (n=509)
30 days
2.9%
90 days
3.8%
180 days
4.9%
360 days
5.1%
Angio-guided (n=496)
FFR assessment → PCI deferred in 37.0% of lsns
Days
Freedom from death, MI, revasc 60
120
180
240
300
360
0.70
0.75
0.80
0.85
0.90
0.95
1.00
MACE 13.2% vs. 18.3%
P=0.02
At 30 days, there is already a absolute diff of 2.9 %, but this is steadily increasing over the year and reaches a value of 5.3% at 1 year
Tonino PAL et al. NEJM 2009;360:213–24 12

14. FAME 1: Relationship Between Visual Angiographic %DS and FFR (n=1,329)
% of lesions:
47%
39%
15%
1.0
0.8
96%
0.6
35%
% lesions with FFR ≤0.80
FFR
80%
0.4
0.2
0.0
50-70%
71-90%
91-99%
Stenosis by angiography (visual assessment)
Tonino PAL et al. JACC 2010;55;

15. Stone GW et al. TCT2012; Submitted.
Correlation Between
QCA DS% and FFR ≤0.80 (n=544)
F1RST
P<0.0001
1/12
16/81
47/237
64/149
28/47
12/15
Stone GW et al. TCT2012; Submitted.

16. How SYNTAX, FREEDOM and FAME should change practice
CABG is superior to first generation DES in complex coronary artery disease ( diabetes)
The heart team should evaluate high-risk pts
Most pts with high Syntax Score should undergo surgery
In other patients PCI is reasonable, but we must do better!
Best in class stents
Optimal pharmacotherapy
Ischemia-guided complete revascularization

17. Study Design WOEST Dewilde W et al. ESC 2012 Inclusion criteria
- Indication for OAC for ≥1 year
- PCI of a single coronary lesion
Study Design
1:1 Randomisation:
Double therapy group:
OAC + 75mg Clopidogrel qd
1 month minimum after BMS
1 year after DES
Triple therapy group
OAC + 75mg Clopidogrel qd + 80mg Aspirin qd
1 month minimum after BMS
1 year after DES
Follow up: 1 year
Primary Endpoint: The occurence of all bleeding events (TIMI criteria) (powered for a reduction from 12% to 5%)
Secondary Endpoints:
Combination of stroke, death, myocardial infarction, stent thrombosis and
target vessel revascularisation
- All individual components of primary and secondary endpoints |

18. Primary Endpoint: TIMI major or minor or minimal bleeding
WOEST: n=583 pts requiring chronic oral anticoagulant therapy
Primary Endpoint: TIMI major or minor or minimal bleeding
Days
Cumulative incidence of bleeding 30 60 90
120
180
270
365
0 %
10 %
20 %
30 %
40 %
50 %
284
210
194
186
181
173
159
140
n at risk:
279
253
244
241
236
226
208
Triple therapy group
Double therapy group
44.9%
19.5%
p<0.001
HR= %CI[ ] |

19. Secondary Endpoint (death, MI, TVR, Stroke, ST)
WOEST
Secondary Endpoint (death, MI, TVR, Stroke, ST)
Days
Cumulative incidence 30 60 90
120
180
270
365
0 %
5 %
10 %
15 %
20 %
284
272
266
261
252
242
223
n at risk:
279
276
273
263
258
234
Triple therapy group
Double therapy group
17.7%
11.3%
p=0.025
HR= %CI[ ]

20. All-Cause Mortality WOEST Triple therapy group Double therapy group
7.5 %
Triple therapy group
Double therapy group
6.4%
HR= %CI[ ]
p=0.027
5 %
Cumulative incidence of death
2.6%
2.5 %
0 % 30 60 90
120
180
270
365
Days
n at risk:
284
281
280
280
279
277
270
252
279
278
276
276
276
275
274
256

21. How WOEST will change medicine
Recent studies have emphasized “stacking” potent therapies, valuing efficacy over safety
The deleterious impact of side-effects such as bleeding have been overlooked
WOEST, by itself, is too small and underpowered to change practice. However…
WOEST is the first of what will hopefully be many studies designed to “peel back” layered therapies, thereby reducing risks and cost

22. Kodali S et al. NEJM 2012:on-line
PARTNER 2A: Study Flow
Randomized = 699 patients
Transfemoral n = 492
TF = 492 (70%)
TA = 207 (30%)
Transapical n = 207
TAVR (244)
AVR (248)
TAVR (104)
AVR (103)
2 Years
Alive = 157
Dead = 74
LTFU = 2
Withdrawal = 2
Censored* = 9
2 Years
Alive = 143
Dead = 80
LTFU = 2
Withdrawal = 16
Censored* = 7
2 Years
Alive = 59
Dead = 42
LTFU = 1
Withdrawal = 0
Censored* = 2
2 Years
Alive = 57
Dead = 34
LTFU = 1
Withdrawal = 8
Censored* = 3
Of the 699 patients in the study, 207 were in the TA arm and 492 were in the TF arm. 2 year follow-up was over 95% in all groups.
95.4% follow-up at 2 years
96.1% follow-up at 2 years
97.1% follow-up at 2 years
95.8% follow-up at 2 years
*Censored = Patient is alive at last contact but no information available within follow-up window
Kodali S et al. NEJM 2012:on-line

23. All-Cause Mortality (ITT)
TAVR
AVR
HR [95% CI] = 0.88 [0.70, 1.12]
p (log rank) = 0.310
35.0%
All-Cause Mortality
26.8%
33.9%
24.3%
The primary analysis reveals no difference in mortality between TAVR and AVR with a hazard ratio of The two year KM estimates of mortality are 35% for AVR and 33.9% for TAVR.
Months
Numbers at Risk
TAVR
348
298
260
234
172 70 31
AVR
351
252
236
217
165 65 32
Kodali S et al. NEJM 2012:on-line

24. All-Cause Mortality or Rehospitalization (ITT)
TAVR
AVR
HR [95% CI] = 0.98 [0.79, 1.21]
p (log rank) = 0.836
46.6%
All-Cause Mortality or Rehospitalization
37.7%
46.5%
34.9%
The KM curve for all cause mortality or repeat hospitalization shows no difference between the two arms with a hazard ratio of 0.98.
Months Post Procedure
Numbers at Risk
TAVR
348
257
223
194
139 48 18
AVR
351
222
200
183
130 53 26

25. Strokes (ITT Population)5 10 15 20 25 30 35
Total 24 20
TAVR
AVR
Number of Events
≤ 30 Days 16 8
TAVR
AVR
> 30 days 8 12
TAVR
AVR
Another way to look at this is to numerically count events. Within 30 days, there are twice as many strokes in the TAVR group reflecting the increased periprocedural risk. However, after 30 days there are numerically more strokes in the AVR group such that the total events over the course of follow-up are 24 in the TAVR group and 30 in the AVR group. Many of these are late events with 5 occurring in the AVR group between 2 and 3 years.
Kodali S et al. NEJM 2012:on-line

26. Mild Paravalvular AR and Mortality TAVR Patients (AT)
None - Trace
Mild
Moderate - Severe
p (log rank) < 0.001
41.7%
Mortality
39.2%
29.5%
29.2%
24.8%
14.5%
When you separate the groups further, it is clear that mortality is being driven by patients with mild AR who have higher mortalities. These curves start to separate in the first year.
Months Post Procedure
Numbers at Risk
None-Tr
167
149
140
126 87 41 16
Mild
136
115 95 86 51 21 10
Mod-Sev 24 19 17 15 13 5 2

27. Implications of PARTNER A at 2 yrs
At many centers TAVR has become the preferred treatment in high-risk patients with aortic stenosis (FDA approved, CMS reimbursed)
- Integrated heart team approach is mandatory
Stroke, vascular complications, and now paravalvular regurgitation remain major issues for TAVR which are being addressed by improved technique, novel device designs and adjunctive devices
The role off TAVR is being explored in moderate-risk pts in ongoing trials

28. RESPECT: Subject Distribution
With cryptogenic stroke within 9 months
TEE with bubble study at 6 months
CARROLL JD et al. NEJM 2013 13
1. Aspirin + clopidogrel was removed from the protocol in 2006 based on changes to the AHA/ASA treatment guidelines

29. 980 pts w/cryptogenic stroke within 9 mos Device Performance (in 499 pts)
Maximum Residual Shunting
at Rest and Valsalva at 6 Months
Grade 0: 72.7%
Grade 1: 20.8%
Grade 2-3: 6.5%
CARROLL JD et al. NEJM 2013
Defined as successful delivery and release of the device for subjects in whom the delivery system was introduced into the body
Defined as successful implantation with no reported in-hospital serious adverse events
Defined as complete obliteration or trivial residual shunting (Grade 0 or I at rest and Valsalva) at 6 months, adjudicated by echo core lab 17

30. 980 pts with cryptogenic stroke within 9 mos Procedure/device-related SAEs
For all AE’s, atrial fibrillation occurred in 3.0% versus 1.5% in the device and medical groups respectively, p=0.13
Pericardial tamponade is a subset of major bleeds, and thus counted in the major bleed category as well
For all SAEs, pulmonary embolism occurred in 1.2% and 0.2% in device and medical groups, respectively, p=0.124
1 case of right atrial thrombus resulted in abandonment of device implant procedure (no device received); 1 case of right atrial thrombus (located inferiorly) not attached to device detected in patient with DVT and PE 4 months after procedure
1 ischemic stroke one week post implant; 1 five months post implant with finding of severe shunting related to previously undiagnosed sinus venosus defect, requiring surgical closure
For all SAEs, there were 3 device group deaths (0.6%) and 6 medical group deaths (1.2%) all of which were not study related, p= 0.334
P-values are calculated using Fisher’s Exact test 16

31. Primary Endpoint Analysis – ITT Cohort 50
Primary Endpoint Analysis – ITT Cohort 50.8% risk reduction of stroke in favor of device
N=980
3/9 device group patients did not have a device at time of endpoint stroke 20
Cox model used for analysis

32. Primary Endpoint Analysis – As Treated Cohort 72
Primary Endpoint Analysis – As Treated Cohort 72.7% risk reduction of stroke in favor of device
N=980
The As Treated (AT) cohort demonstrates the treatment effect by classifying subjects into treatment groups according to the treatment actually received, regardless of the randomization assignment 22
Cox model used for analysis

33. Subpopulation Differential Treatment Effect24

34. How will RESPECT change practice?
The rates of follow-up stroke were low; PFO closure is not required in most patients with cryptogenic stroke, especially if the shunt is small
A comprehensive work-up for other causes of stroke should be performed, such as concealed paroxysmal atrial fibrillation
PFO closure may be appropriate for selected pts, such as large shunt, large or recurrent stroke, or anticoagulant ineligible
New therapies (drugs and devices) should not be widely adopted without positive demonstration of clinical benefit in RCT(s)

35. Top ACC Late Breaking Trials
PREVAIL: LAA closure with the Watchman as an alternative to OAC
PARTNER 2, Cohort B: SAPIEN XT vs. standard of care in inoperable pts with aortic stenosis
CHAMPION PHOENIX: Cangrelor in patients undergoing PCI
STREAM: Pharmacoinvasive strategy in STEMI pts with delay to primary PCI