CTSN Trials of Mitral Valve Repair and Replacement

CTSN Trials of Mitral Valve Repair and Replacement Michael Mack, M. D. Baylor Scott & White Health Dallas, TX

Conflict of Interest Disclosure • Co- PI of COAPT Trial of Abbott Vascular • Co-PI of the PARTNER 3 Trial of Edwards Lifesciences • Executive Committee Intrepid Trial of Medtronic

What is CTSN? • Cardiothoracic Surgical Trials Network • Goal – Evaluate surgical approaches to cardiovascular disease • Support- $50 M (2013 -2018); $70 M (2019 -2025) – NIH • NHLBI • NINDS – CIHR- Canadian Institute of Health Research • PI’s – Richard Weisel-Toronto – Patrick O’Gara-Boston

35 Study Sites CTSN Collaborators Broad US & Canadian Involvement

CTSN Collaborators German Sites-19 Germany

CTSN Accomplishments Comprehensive Research Agenda

CTSN Completed and Ongoing Trials MPC/LVA D 05/12 – 06/13 SMR 12/08 – 06/13 MMR 01/09 -06/14 AF 01/10 -10/14 POAF 05/14 -05/155 Neuro* 03/15 -07/16 MPC/LVAD II 05/15 - ongoing LTMR 4/17 ongoing Hybrid 07/17 TR 05/16 - ongoing VEST 2010 * Halted for futility 2008 2009 2011 2012 2013 2014 2015 2016 2017 10/17 2018 2019

CTSN Accomplishments Efficient and Timely Enrollment Observational Studies >14, 000 pts RCTs 2054 pts 253 523 383 189 147 AF MM Ab R la tio Ne n ur op PO M ro AF PC te LV ctio AD n I& II TV R 251 301 260 SM Randomized 8000 6000 R 600 500 400 300 200 100 0 Target Enrollment 4000 2000 0 6877 5158 2109 Infection Cohort Hybrid Enrollment Predictors POAF

CTSN Impact Publications

Ischemic MR • Severe MR: – Mitral valve repair with annuloplasty vs. mitral valve replacement with complete preservation of the subvalvular apparatus. • Moderate MR: – Mitral valve repair combined with coronary artery bypass grafting vs. coronary artery bypass grafting alone

SMR Trial Design

Primary Endpoint • Degree of left ventricular reverse remodeling − Assessed by left ventricular end systolic volume index (LVESVI) using TTE at 12 months

Change in LVESVI 2 (ml/m ) Time Repair Replace Baseline 61. 1 ± 26. 2 65. 7 ± 27. 4 12 months 54. 6 ± 25. 0 60. 7 ± 31. 5 p=0. 18

Mortality 12 Month Mortality: 14. 2% (repair) vs. 17. 6% (replacement), p =0. 47 30 Day Mortality: 1. 6% (repair) vs. 4. 0% (replacement), p =0. 26

MACCE at 12 Months

Serious Adverse Events 120 Repair Replacement Overall SAE Rate (100 -pt years) 202. 1 (repair) vs. 189. 0 (replacement) p=0. 49 80 60 40 P=NS 20 P=NS ns ita os p -H Re Lo ca liz ed In liz fe at io ct io n ng di ee pe r -o Re V M Bl at io n ro ke St ar t. F ai lu re 0 He Rate (100/pt-yrs) 100 P=NS

Recurrent MR at 1 year Moderate or Severe Recurrent MR Percent with moderate or severe recurrent MR 35 32. 6 30 25 20 p < 0. 001 15 10 5 2. 3 0 Repair Replacement

LVESVI with Recurrent MR Mean LVESVI for Patients Undergoing Repair 70 p < 0. 001 60 Mean LVESVI 50 40 Baseline 30 12 Months 20 10 0 Repair with MR Repair without MR

November 18, 2013, at NEJM. org.

• J Thorac Cardiovasc Surg 2015; 149: 752 -61)

Predictors of Recurrence

Predictors of Recurrence Tenting Area Tenting Height Anterior and Posterior Leaflet Angles

Predictors of Recurrent MR After MVA No or Mild annular dilatation Coaptation depth >1 cm Posterior leaflet angle >45° Distal anterior leaflet angle >25° Advanced LV remodelling LVEDD > 65 mm Systolic sphericity index > 0. 7 End systolic interpapillary muscle distance >20 mm LVESV ≥ 145 ml (or ≥ 100 ml/m 2)

Rates of Mitral Valve Repair and Replacement for Severe IMR in the US: What is the Impact of the CTSN Trial on Clinical Practice? • Thourani VH, Vemulapalli S, Gelijns AC, Moskowitz AJ, Acker M, Woo J, Zhang S, Gammie JS, O’Gara PT, Ailawadi G, Moon M, Jung S, Badhwar V, Adams D, Suri RM, Bolling S, Gillinov AM, Michler RE, Smith PK, Perrault LP, Goldstein D, Argenziano M, Bavaria J, Bafi A, Jacobs J, Miller M, Weisel RD, and Mack MJ 55 th Annual Scientific Meeting of the Society of Thoracic Surgeons January 29, 2018

Objectives • Assess relative rates of MV repair vs replacement for severe IMR before and after publication of CTSN trial outcomes • Explore whether change in surgical practice is associated with changes in 1 -year clinical outcomes

Methods January 2014 2011 – 2013 (Pre CTSN Publication April 2014 – 2016 (Post CTSN Pub) Chronic IMR MVRepair vs MVReplace 4 Month Blanking Period For Clinical Adoption 1. Trends and rate of MVRe vs. MVReplace 2. 1 year outcomes A. Mortality B. Heart failure readmission VS 1. Trends and rate of MVRe vs. MVReplace 2. 1 year outcomes A. Mortality B. Heart failure readmission

Trends of MV Repair vs Replacement: All Patients (n=4, 440) Pre CTSN Publication Post CTSN Publication MV Repair (n=1, 414) MV Repair (n=1, 721) P = NS MV Replacement (n=550) P <0. 0001 MV Replacement (n=755)

Trends of CABG + MV Repair vs Replacement (n=2, 459) Pre CTSN Publication Post CTSN Publication CABG+MV Repair (n=763) CABG+MV Repair (n=918) P = NS P <0. 0001 CABG+MV Replacement (n=320) CABG+MV Replacement (n=458) *4. 6% underwent CABG alone *4. 8% underwent CABG alone

Mortality: CMS-linked Patients P=0. 814 Pre Post

HF Readmissions: CMS-linked Patients P < 0. 001 Pre Post

Adjusted 1 -Year Clinical Outcomes Outcome Mortality Main Post vs Pre HF-Readmission Post vs Pre *p<0. 05 Unadjusted HR Adjusted HR (95% CI) 0. 97 ( 0. 72, 1. 29) 0. 94 ( 0. 69, 1. 27) 0. 51 (0. 36, 0. 7) 0. 53 (0. 38, 0. 75)*

Conclusions • There is significant early impact of CTSN publication on surgical practice patterns with a decrease, but not elimination of MV repair for severe IMR • No temporal difference in mortality within the 2 time periods • Temporal reduction in HF readmissions • Exceeding background impact of improvements in patient (including HF) management • Presumably from an improvement in patient selection as potentially learned from the CTSN trial

Transcatheter MV Repair: Device Landscape 2018 Gregg Stone Edge-to-edge • Mitra. Clip*** • Mitra. Flex MV replacement (cont) • Edwards Cardi. AQ* • Mitral. Heal • Edwards Fortis* • HT Consultant Saturn Coronary sinus annuloplasty • Neovasc Tiara* • Lutter valve • Cardiac Dimensions Carillon** • Abbott Tendyne* • Transcatheter Technologies • Cerclage annuloplasty • Medtronic Intrepid* Tresillo • High. Life* • Venus Direct annuloplasty and • MValve* • Verso basal ventriculoplasty • Caison* • Transmural Systems • Mitralign TAMR** • NCSI Navi. Gate • Valtech Cardioband** Other approaches • St. Jude • GDS Accucinch* • Neo. Chord DS 1000** • Micro Interventional • Harpoon neochords* • Millipede IRIS* • Valtech Cardio. Valve • MVRx ARTO* • Babic chords* • Valve. Xchange • Mardil BACE* • Middle Peak Medical* • Mitr. Assist • Mitraspan* • St. Jude leaflet plication* • Braile Quattuor • Valcare Amend* • Cardiosolutions Mitra • Cephea • Micardia en. Cor Spacer* • Direct Flow • Cardiac Implants RDS • Valtech Vchordal • Sinomed Accufit • Quantum. Cor (RF) • Mitralix

Implications for TMVR/R • The high incidence of recurrent MR at 2 years portends continued progression of ventricular remodeling. • A “no leak” repair in IMR (thus positive remodeling) should render better results than a replacement. • Global dysfunction with apico-lateral displacement of papillary muscles portends a poor repair – due to leaflet tethering • A MVR chord sparing MVR is better than a failed mitral repair • All viable ischemic myocardium must be revascularized • RCTs suggest that MVR no riskier than a MVRep in SIMR • Method selection should be based on pathologic anatomy • Wait on COAPT trial results to see if fixing the MR really helps survival or QOL.

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