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

Disclosures Medtronic Speaker/Training Estech Consultant SJD Medical Advisory Board

Thank You Marc Gillinov MD for providing slides

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

Easy…….. Actually very easy So why surgeon wouldn’t use it? Eur J Cardiothorac Surg. 1995;9(11):621-6 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

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

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

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?

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

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

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

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

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

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

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

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

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

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 178-41-31=106 (60%) Sixty percent have MR < 2+ at 1 year

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)

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)

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+ 178-41-31-40=66 (37%) Thirty-seven percent have MR < 2+ at 1 year

Long-term outcome after mitral valve repair: a risk factor analysis. Eur J Cardiothorac Surg. 2007 Aug;32(2):301-7. 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. 2006 Sep;82(3):819-26. 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.

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%

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

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

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

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

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_20090917.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

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_20090917.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

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

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

30 Day Modified * MAE Intent to Treat, Hierarchical Events Safety endpoint met with a wide margin pSUP<0.00001 42.6% 8.3% Device Control *Major bleeding requiring transfusion ≥ 2U, or surgical intervention.

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.

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

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

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