1. Debate - EVEREST and Residual Mitral Regurgitation: Percutaneous Mitral Devices Will Change the Indications for Mitral Valve Procedures
Niv Ad, MD
Chief, Cardiac Surgery
Professor of Surgery, VCU
Inova Heart and Vascular Institute
Washington DC Metropolitan Area

2. Disclosures Medtronic Speaker/Training Estech Consultant SJD Medical
Advisory Board

3. Thank You
Marc Gillinov MD for providing slides

4. What is not going to be discussed
The Surgical “Edge to Edge” MV repair

5. Easy…….. Actually very easy So why surgeon wouldn’t use it?
Eur J Cardiothorac Surg. 1995;9(11): Improved results with mitral valve repair using new surgical techniques. Fucci C, Sandrelli L, Pardini A, Torracca L, Ferrari M, Alfieri O.
Easy…….. Actually very easy
So why surgeon wouldn’t use it?
Doesn’t work as well
Physiology

6. What is not going to be discussed
The Surgical “Edge to Edge” MV repair
What is the real data concerning the Heart Lung Machine

9. Everest II First randomized trial of mitral valve surgery
First randomized trial of percutaneous mitral valve repair
Groundbreaking
Provides a great deal of data
Raises many questions

10. Four Areas of Question Trial design
What was the approach in the surgical arm?
What are “intention to treat” and “per protocol” analyses?
Is the MitraClip effective?
Can the mitral valve be repaired if the MitraClip fails?
Why is surgical safety so poor in this trial?

11. EVEREST II Randomized Clinical Trial
Surgical and Percutaneous Therapy for
Mitral Regurgitation
Mitral Valve Surgery
Repair/ Replacement
Catheter Based Mitral Valve Repair
MitraClip® System or
Small—only 95 patients
Sternotomy in all patients
No less invasive approaches

12. Less Invasive Surgery vs. Sternotomy
Superior
Blood loss
Postoperative pain control
Length of stay
Cosmesis
Patient satisfaction
Equivalent
Safety
Repair rate
Repair durability

13. Intention to treat vs. Per protocol
Trial Design
Intention to treat vs. Per protocol

14. Trial Populations (Gregg Stone, MD)
Intention to treat: All pts randomized, regardless of whether or not procedure was successful (or even performed), and regardless of whether pt crossed over to another therapy
Modified intention to treat: All pts randomized and treated by an initial therapy, regardless of initial success or crossovers
As treated: All pts analyzed according to the acute treatment performed regardless of randomization or procedural success
Per protocol: Pts in whom major protocol violations or deviations did not occur
Everest definition: Pts assigned to the MitraClip in whom acute procedural success was achieved, and those assigned to surgery in whom surgery was performed

15. EVEREST II RCT: Patient Flow
Randomized Cohort n=279
Device Group
n=184
Control Group
n=95
Randomized, not treated
Device, n=6
Control, n=15
Treated
n=178
Treated
n=80
(86% MV repair)
30 days
n=136
99% Clinical Follow-up
n=79
Acute Procedural Success
Not Achieved
n=41*
*20 of 41 no implant
Acute Procedural Success
Achieved
n=137
Acute Procedural Success (APS) = MR ≤2+ at discharge
12 months
n=134
98.5% Clinical Follow-up
98% Echo Follow-up
n=74
94% Clinical Follow-up
92% Echo Follow-up

16. EVEREST II RCT: Patient Flow
Randomized Cohort n=279
Device Group
n=184
Control Group
n=95
Randomized, not treated
Device, n=6
Control, n=15
Treated
n=178
Treated
n=80
(86% MV repair)
30 days
n=136
99% Clinical Follow-up
n=79
Acute Procedural Success
Not Achieved
n=41*
*20 of 41 no implant
Acute Procedural Success
Achieved
n=137
23%
12 months
n=134
98.5% Clinical Follow-up
98% Echo Follow-up
n=74
94% Clinical Follow-up
92% Echo Follow-up

17. Is the Clip Effective?
Yes, in many people
In how many?

18. Primary Effectiveness: Endpoint Components
12 Month Endpoint Components
% Patients experiencing event
Device Group
(n=134)
Control Group
(n=74)
p-value
Death
4.5%
6.8%
0.5260
MV Surgery or
Re-operation for MV dysfunction
6.7%
2.7%
0.3344
MR>2+
16.4%
0.0026
Total
27.6%
12.2%
Difference Device-Control 15.4%
(90% two-sided Conf Int: 5.4%, 25.4%)
Primary driver for failure in effectiveness in PP Device group is due to MR
Primary driver for failure in effectiveness in PP Control group is death

19. Primary Effectiveness: Endpoint Components
12 Month Endpoint Components
% Patients experiencing event
Device Group
(n=134)
Control Group
(n=74)
p-value
Death
4.5%
6.8%
0.5260
MV Surgery or
Re-operation for MV dysfunction
6.7%
2.7%
0.3344
MR>2+
16.4%
0.0026
Total
27.6%
12.2%
Difference Device-Control 15.4%
(90% two-sided Conf Int: 5.4%, 25.4%)
Primary driver for failure in effectiveness in PP Device group is due to MR
Primary driver for failure in effectiveness in PP Control group is death
31 Patients

20. Modified Intention to Treat Analysis
Let’s Do the Math
Modified Intention to Treat Analysis
178 “treated” with MitraClip
41 without acute procedural success
31 with MR >2+ or mitral operation
=106 (60%)
Sixty percent have MR < 2+ at 1 year

21. MR Reduction :Baseline vs 12 Months, Per Protocol Surgery more often achieves lower degree of residual MR
p<0.0001
1+-2+
7.7% (1/13) Replacement 2+ 2+ 0+ 1+
36.1%
17.4%
18.4% (7/38) Replacement
58.2% 3+
1+-2+
11.8% 1+ 3+
33.6% 2+
P-value: Fishers’ Exact used
1+-2+
8.7% 4+ 3+
16.0% 2+
13.4% 4+
2.5% 3+
3.0% 4+
(n=119)
(n=119)
(n=67)
(n=67)
Device
Control
p-value compares the distribution of MR grade in device with the distribution of MR grade in control at 12 months (Fishers’ Exact test)

22. MR Reduction :Baseline vs 12 Months, Per Protocol Surgery more often achieves lower degree of residual MR
p<0.0001
1+-2+
7.7% (1/13) Replacement 2+ 2+ 0+ 1+
36.1%
17.4%
18.4% (7/38) Replacement
58.2% 1+ 3+
1+-2+
11.8% 3+
40 pts
33.6% 2+
P-value: Fishers’ Exact used
1+-2+
8.7% 4+ 3+
16.0% 2+
13.4% 4+
2.5% 3+
3.0% 4+
(n=119)
(n=119)
(n=67)
(n=67)
Device
Control
p-value compares the distribution of MR grade in device with the distribution of MR grade in control at 12 months (Fishers’ Exact test)

23. Modified Intention to Treat Analysis
More Math
Modified Intention to Treat Analysis
178 “treated” with MitraClip
41 without acute procedural success
31 with MR >2+ or mitral operation
40 have MR = 2+
=66 (37%)
Thirty-seven percent have MR < 2+ at 1 year

24. Long-term outcome after mitral valve repair: a risk factor analysis.
Eur J Cardiothorac Surg Aug;32(2): Epub 2007 Jun 11.
Long-term outcome after mitral valve repair: a risk factor analysis.
Meyer MA, von Segesser LK, Hurni M, Stumpe F, Eisa K, Ruchat P.
Ann Thorac Surg Sep;82(3):
Survival advantage and improved durability of mitral repair for leaflet prolapse subsets in the current era.
Suri RM, Schaff HV, Dearani JA, Sundt TM 3rd, Daly RC, Mullany CJ, Enriquez-Sarano M, Orszulak TA.

25. EVEREST II RCT: Endpoints
Analysis
Endpoint Met
Safety, 30 day Major Adverse Event Rate, Per Protocol
YES
MitraClip device patients: 9.6%
MV surgery patients: 57%
Safety, 30 day Major Adverse Event Rate, Intent To Treat
MitraClip device patients: 15%
MV surgery patients: 48%
Effectiveness, 12 mo Clinical Success Rate, Per Protocol
MitraClip device patients: 72%
MV surgery patients: 88%
Effectiveness, 12 mo Clinical Success Rate, Intent to Treat
MitraClip device patients: 67.4%
MV surgery patients: 73.0%

26. Conclusion
The MitraClip procedure demonstrated safety through 12 months.
The MitraClip procedure is a safe therapeutic option for selected patients with significant mitral regurgitation.

27. My Conclusion Trial design
May not have included the “best” of surgery (i.e. less invasive approaches)
Small number in surgical group
Confusion with intent to treat vs. per protocol analyses

28. My Conclusion Effectiveness of MitraClip
37% of MitraClip patients had MR < 2+ at 1 year with MitraClip alone

29. What can we learn from a 1 year follow-up?

30. Cardiac Death to 3 Years 3VD Subset
TAXUS (N=546)
CABG (N=549)
P=0.01 20 40
Before 1 year*
1.9% vs 3.5%
P=0.12
1-2 years*
0.4% vs 1.0%
P=0.45
2-3 years*
0.6% vs 1.8%
P=0.09
Cumulative Event Rate (%)
1 yr data From SYNTAX_CSR_randomized_Unblinded_2008Oct10.doc exhibit 53
2-Year_Randomized_ doc Exhibits 23
SYNTAX 3-Year Report_Randomized_12JUL10.doc exhibits 23 (KM overall rate), 24 (year 2-3)
6.2%
2.9% 12 36 24
Months Since Allocation
Cumulative KM Event Rate ± 1.5 SE; log-rank P value; *Binary rates
ITT population 30

31. CVA to 3 Years 3VD Subset TAXUS (N=546) CABG (N=549) P=0.64 20 40
Before 1 year*
1.9% vs 0.7%
P=0.09
1-2 years*
0.4% vs 0.8%
P=0.69
2-3 years*
0.6% vs 0.8%
P=1.00
Cumulative Event Rate (%)
1 yr data From SYNTAX_CSR_randomized_Unblinded_2008Oct10.doc exhibit 53
2-Year_Randomized_ doc Exhibits 23
SYNTAX 3-Year Report_Randomized_12JUL10.doc exhibits 23 (KM overall rate), 24 (year 2-3)
2.9%
2.6% 12 36 24
Months Since Allocation
Cumulative KM Event Rate ± 1.5 SE; log-rank P value; *Binary rates
ITT population 31

32. My Conclusion Surgical valve repair after MitraClip 50/50 proposition
Challenging

33. My Conclusion Safety endpoints weighted toward MitraClip
“Transfusion problem”
But it is less invasive than surgery

34. 30 Day Modified * MAE Intent to Treat, Hierarchical Events Safety endpoint met with a wide margin
pSUP<
42.6%
8.3%
Device
Control
*Major bleeding requiring transfusion ≥ 2U, or surgical intervention.

35. Cardiac Surgery - % of Pump Cases Receiving Any Blood Products Intraop and/or Postop (RBCs, Platelets, FFP, Cryo) Inova Fairfax Hospital Only By Month 2010
Only 5.9%>1U
Master Source File: Blood_Products_And_Reops_Monthly_Revised.xls
Shared Directory: Shared\COA\Outcomes\STS Adult Surgery
Worksheet: Percent_Recv Blood CHARTS.

36. My Conclusion Safety endpoints weighted toward MitraClip
“Transfusion problem”
But it is less invasive than surgery
Surgeons must strive to reduce
Invasiveness
Morbidity

37. My Final Conclusions
Unclear how etiology (functional vs. degenerative) influences results
Today a reasonable option in patients at high surgical risk (denied surgery)
Results will likely improve with time and experience

38. MV Procedures Should Attempt to Actually Repair the Mitral Valve
Thank You
Oh… Don’t Forget !!
MV Procedures Should Attempt to Actually Repair the Mitral Valve