2-Year Outcomes following Surgical Treatment of Moderate Ischemic Mitral Regurgitation: The Cardiothoracic Surgical Trials Network Robert E. Michler, M.D. For the CTSN Investigators ACC Featured Clinical Research April 3, 2016 Distinguished panel and guests, it is my privilege to deliver on behalf of the NIH and CIHR-sponsored Cardiothoracic Surgical Trials Network and its investigators the 2 year results of a randomized clinical trial for the surgical treatment of moderate ischemic mitral regurgitation `

The Many Faces of MR Primary MR Secondary MR Structural (degenerative) valve and sub-valvular disease Secondary MR Functional Impairment of the LV Ischemic Non-Ischemic Mitral regurgitation is either Primary, related to structural and degenerative disease of the valve and the sub-valvular apparatus Or Secondary, related to regional or global functional impairment of the left ventricle from ischemic or non-ischemic disease.

Epidemiology of Ischemic MR 50% of MI is associated with at least mild MR 10% of MI is associated with moderate ischemic MR Ischemic MR is associated with reduced event-free survival Half of all MI’s are associated with some degree of mitral regurgitation and 1 in 10 are associated with Moderate MR. The presence of any degree of ischemic MR identifies patients with LV dysfunction who have a higher mortality risk than those without MR, regardless of the treatment. Bursi F et al. Circulation 2005;111:295-301 Perez de Isla L et al. . Eur Heart J 2007;28:2866-2872 Grigioni F et al. J Am Coll Cardiol 2005;45:260-267

Surgical Treatment Options Surgery for Moderate ischemic mitral regurgitation includes coronary artery bypass surgery alone or CABG plus mitral valve repair with an annuloplasty ring. Proponents of CABG alone argue that revascularization may improve regional LV function and reduce LV chamber size, thereby restoring the functional integrity of the subchordal apparatus. Proponents for mitral-valve repair in addition to CABG cite the adverse consequences of persistent ischemic MR and argue that mitral-valve repair may prevent progressive adverse remodeling, improve cardiac function, and reduce the risk of heart failure. The evidence base supporting either therapy is conflicting, limited in quality, and is associated with therapeutic uncertainty and practice variation. Considerations: CABG alone: can improve LV function and MR CABG + MVr: may reduce adverse consequences of MR

CTSN Moderate MR Trial Design Patients Screened for Moderate Ischemic MR Randomized Patients (n=301) CABG Alone (n=151) CABG + Valve Repair Undersized Ring (n=150) The Cardiothoracic Surgical Trials Network randomized 301 patients with Moderate mitral regurgitation to receive CABG alone or CABG plus mitral valve repair with an undersized complete annuloplasty ring. Outcomes were measured at 6 months, 1 year and 2 years. Outcomes Measured at 6, 12 and 24 months Primary Endpoint Analysis (n=301)

Two-Year Endpoints Primary: LVESVI Secondary: Mortality MR grade and regional wall motion MACCE Serious adverse events Readmissions QOL The Primary Endpoint was the degree of left ventricular reverse remodeling as defined by changes in LV end-systolic volume index. Secondary end points included mortality, MR grade and regional wall motion, a composite of major adverse cardiac or cerebrovascular events,, serious adverse events, readmissions, and quality of life.

Integrative Method of MR Grading (ASE Guidelines: Zoghbi W. et al Integrative Method of MR Grading (ASE Guidelines: Zoghbi W. et al. JASE 2003; 16:777-802) Parameter Mild Moderate Severe EROA(cm2) <0.2 0.2 - 0.39 ≥0.4 VC width (mm) <3 3 - 6.9 ≥7 Jet/LA area <20% 20-39% ≥ 40% Vena Contracta Jet area/LA Ratio EROA Mitral regurgitation was consistently measured in a Core Echo Lab. An Integrative Method was utilized in which Moderate ischemic mitral regurgitation was defined using the effective regurgitant orifice area, vena contracta width, and the ratio of MR jet area to left atrial area. At baseline, 93% of patients had Moderate MR, 4% Severe MR and 3% Mild MR.

Change in LVESVI at 2 Years Median with 95% CI for change in LVESVI (2 Year – baseline) Z = 0.38, p = 0.71 (All Patients) At baseline, the mean LV end-systolic volume index was 55 ml/m2 in the CABG alone group and 60 ml/m2 in the combined-procedure group.   The results for all patients is shown on the left side of the graph while the changes seen in 2-year survivors appears on the right. At the 2-year endpoint, there was modest reverse remodeling for both CABG alone and CABG + repair cohorts, and the mean reduction from baseline to 2 years was approximately 14 ml/m2 for both groups.

Mortality The overall conduct of surgery was excellent. 2 Year Mortality: 10.6% (CABG) vs. 10% (CABG+Repair), p =0.86 1 Year Mortality: 7.3% (CABG) vs. 6.7% (CABG+Repair), p =0.83 The overall conduct of surgery was excellent. At 30 days, mortality for CABG alone was 2.7% and for the combined-procedure was 1.3%. At 2 years, mortality for CABG alone was 10.6% and for the combined-procedure 10%. Neither difference was significant.

MACCE At 2 years, there was no difference in the composite endpoint of major adverse cardiac or cerebrovascular events, or its individual components of death, stroke, subsequent mitral valve surgery, or readmission for heart failure.

Overall SAE Rate by 2 years: Rates of Serious Adverse Events and Re-hospitalization Rate per 100-pt yrs Overall SAE Rate by 2 years: CABG: 30.6 vs. CABG + MV Repair 25.8 P = 0.35 P=NS The total number of serious adverse events was similar for the two treatment groups at 2 years, However, the rate of all serious neurologic adverse events, which included stroke, transient ischemic attack, seizures, and metabolic encephalopathy, was significantly higher in the CABG plus MV repair group. All of these events occurred within the first year. The stroke rate between groups was not significant. The rate of supraventricular arrhythmias was significantly higher in the the CABG plus MV repair group, with these events occurring at the time of surgery. Heart Failure All Neurological Stroke Bleeding Supraventricular Re-hospitalizations Events Arrhythmia *P-values based on overall rates from baseline to 2 years

Quality of Life at 2 years (DASI) The DASI Score, which is a measure of cardiac functional activity, demonstrated a significant improvement at 2 years with CABG + MV repair, suggesting an increased ability to undertake tasks with higher metabolic demands.   In both groups of patients at 2 years, there was equivalent improvement over baseline in physical health and there was a reduction from baseline in heart-failure as measured by both the SF-12 physical function scale and the Minnesota Living with Heart Failure questionnaire. *SF-12 Physical Health Score, SF-12 Mental Health Score and MLHF were not significantly different between the groups

MR Persistence (≥ moderate) At 2 years, 31% of the CABG alone group had persistent or recurrent moderate MR and 2% of these patients progressed to severe MR, whereas no patient progressed to severe MR in the repair group, with 11% of repair patients having moderate MR. Significant improvement in MR was seen in both groups with 89% of the CABG + repair group having no, trace or mild MR, compared to 68% in the CABG alone group.

Wall Motion Segment Scores at Baseline 17 (1 . 8 7 ) 16 (2 4 2 15 (1.76) 14 .67) 13 (1.83) 12 .72 11 6 4) 10 ( 2. 49) 9 5 9) 44 1. 57) (1.80) 83 42) 3 1 40) To explore the effect of revascularization on the risk of persistence of mitral regurgitation, we analyzed changes in echocardiographic wall-motion in a 17 segment model. Worse wall motion is depicted in red and better wall motion is in green. The inferior–posterior–lateral region is depicted in the segments outlined in yellow. These regions were abnormal at baseline with no difference between treatment groups. All Patients w/ MR data at 2 Years ≥ 2.36 1.98 - 2.35 1.71 - 1.97 1.47 - 1.70 1.31 - 1.46 ≤ 1.30 Worse Better

Wall Motion Segment Scores at 2 Years 17 (1 . 4 8 ) 16 9 15 (1.34) 14 .38) 13 (1.58) 12 .48 11 (2 2 4) 10 ( 1. 72) 2) 21 7 35) 6 (1.71) 5 77 94) 3 1 22) 17 (1 . 37 ) 16 9 3 15 (1.30) 14 .26) 13 (1.37) 12 .42 11 (2 2 8) 10 ( 2. 19) 8 19 7 1. 6 (1.67) 5 88 4 35) 1 16) Wall motion scores appreciably improved for patients free of moderate or severe mitral regurgitation at 2 years. In contrast, the wall-motion scores for patients “With” persistent Moderate or Severe MR did not appreciably improve at 2 years. No Moderate or Severe MR at 2 Years Moderate or Severe MR at 2 Years ≥ 2.36 1.98 - 2.35 1.71 - 1.97 1.47 - 1.70 1.31 - 1.46 ≤ 1.30 Worse Better

Limitations Primary end point not a clinical endpoint Trial with mortality endpoint would require several thousand patients and multiple years of follow up Follow up is limited to 2 years 5 year follow up is planned There are several limitations in this study.   The first is that the trial did not measure a Primary Clinical endpoint such as death because this would have required several thousand patients and multiple years of follow up. The second limitation is that only the 2 year results are reported. We plan to follow these patients for 5 years.

Summary No difference in degree of LV reverse remodeling at 2 years CABG + MV repair associated with significantly less persistent MR at 2 years Freedom from persistent MR at 2 years correlated with improved inferior-posterior-lateral wall motion regardless of treatment arm In Summary, there was no difference at 2 years in the primary endpoint of LV reverse remodeling CABG plus a restrictive annuloplasty was associated with a more durable correction of moderate ischemic MR Freedom from persistent or recurrent MR at 2 years correlated with improvement in inferior-posterior-lateral wall motion regardless of treatment arm

Summary CABG + MV repair provided a more durable correction of MR, but there was no difference at 2 years in: Mortality MACCE Hospital readmissions CABG + MV repair had early risk of more neurological and supraventricular arrhythmia events While CABG + Restrictive annuloplasty repair provided a more durable correction of MR, there was no difference at 2 years in: Mortality, MACCE or Hospital readmissions CABG + MV repair manifest an early hazard of more neurological and supraventricular arrhythmia events

Conclusion Improvement of Inferior-Posterior-Lateral regional function by revascularization is associated with resolution of IMR, with or without MV repair. At 2 years, there was no clinically meaningful advantage to the routine addition of MVr to CABG in patients with Moderate ischemic MR Improvement in Inferior-Posterior-Lateral regional function by revascularization is associated with resolution of ischemic MR, with or without MV repair. At 2 years, there was no clinically meaningful advantage to the routine addition of a restrictive annuloplasty MV repair to CABG in patients with ischemic moderate MR

MMR Investigators Data Coordinating Center: InCHOIR Montefiore – Einstein Emory University Duke University Hôpital Laval University of Virginia Health System Montreal Heart Institute University of Pennsylvania Columbia University Medical Center Cleveland Clinic Foundation University of Maryland Brigham and Women's Hospital Sacré-Cœur de Montréal Ohio State University Medical Center East Carolina Heart Institute Wellstar / Kennestone Baylor Research Institute University of Southern California St. Michael’s Hospital Toronto General Hospital Mission Hospital NIH Heart Center at Suburban Hospital Inova Heart & Vascular Institute University of Alberta Hospital Centre Hospitalier de l'Université de Montréal Sunnybrook Health Sciences Centre Aarhus University We wish to thank the many Investigators who participated in the CTSN Trial of Moderate Ischemic Mitral Regurgitation and

Acknowledgements Supported by U01 HL088942 Cardiothoracic Surgical Trials Network (CTSN) Funding Agencies: National Heart, Lung, and Blood Institute National Institute of Neurological Disorders and Stroke Canadian Institutes for Health Research We wish to acknowledge the leadership and support of the National Heart, Lung, and Blood Institute, the National Institute of Neurological Disorders and Stroke, and the Canadian Institutes for Health Research.

The manuscript is available on-line in the New England Journal of Medicine.