Online Appendix for the following jacc article title




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4/22/2016

Online Appendix for the following JACC article

TITLE: Outcomes of the RESTOR-MV (Randomized Evaluation of a Surgical Treatment for Off-Pump Repair of the Mitral Valve) Trial
AUTHORS: Eugene A. Grossi, MD, Nirav Patel, MD, Y. Joseph Woo, MD, Judith D. Goldberg, ScD, Charles F. Schwartz, MD, Valavanur Subramanian, MD, Ted Feldman, MD, Robert Bourge, MD,‌‌‌ Norbert Baumgartner, MD, Christopher Genco, MD, Scott Goldman, MD, Marco Zenati, MD, J. Alan Wolfe, MD, Yugal K. Mishra, MD, Naresh Trehan, MD, Sanjay Mittal, MD, Shulian Shang, Todd J. Mortier, Cyril J. Schweich, Jr., MD, for the RESTOR-MV Study Group
Appendix A: RESTOR-MV Trial Participants and Details

RESTOR-MV Investigational Sites

Site

PI

Aspirus Wausau Hospital (WI)

Fernando Riveron, MD

Baystate Medical Center (MA)

John Rousou, MD

Covenant Healthcare Medical Center (MI)

Norbert Baumgartner, MD

Duke University (NC)

R. Duane Davis, MD

Emory University (GA)

Thomas Vassiliades, MD

Enloe Medical Center (CA)

Li Poa, MD

Escorts Heart Institute and Research Centre (India)

Yugal Mishra, MD

Geisinger Health System (PA)

Alfred Casale, MD

Hospital of the University of Pennsylvania (PA)

Y. Joseph Woo, MD

Indraprastha Apollo

Naresh Trehan, MD / Sanjay Mittal, MD

Lankenau Hospital (PA)

Francis Sutter, MD / Scott Goldman, MD

Lenox Hill Hospital (NY)

Valvanur Subramanian, MD / Nirav Patel, MD

Nebraska Heart Institute Lincoln (NE)

James Wudel, MD

Nebraska Heart Institute Omaha (NE)

Deepak Gangahar, MD

New York University Hospital - Tisch (NY)

Eugene Grossi, MD

New York University Medical Center - VA (NY)

Eugene Grossi, MD

Northwest Surgical Associates / Legacy (OR)

Thomas Malloy, MD

Prairie Education and Research Cooperative (IL)

Carl Arentzen, MD

Rhode Island Hospital (RI)

Arun Singh, MD

Spectrum Health (MI)

Charles Willekes, MD

St. Joseph Mercy Hospital (MI)

Benjamin McCallister, MD

St. Joseph’s (MD)

Kimble Jett, MD / John Laschinger, MD

St. Joseph’s Hospital and Medical Center (AZ)

Michael Caskey, MD

St. Joseph’s Hospital of Atlanta (GA)

J. Allan Wolfe, MD

St. Luke’s Hospital (PA)

Terrence Theman, MD

St. Luke’s (WI)

David Kress, MD

Stony Brook University Hospital (NY)

Thomas Bilfinger, MD / Todd Rosengart, MD

The Cleveland Clinic Foundation (OH)

Tomislav Mihaljevic, MD

VA Pittsburgh Healthcare System (PA)

Marco Zenati, MD


RESTOR-MV Echocardiographic Core Lab: Mayo Clinic:

Jay Oh, MD, Mayo Clinic, Rochester, MN

Steve Omen, MD, Mayo Clinic, Rochester, MN

The Echocardiographic Core Lab graded MR according to the ACC/ASE Guidelines, Journal of American Society of Echocardiography 2003


RESTOR-MV Trial Clinical Events Committee (CEC):

Emil Missov, MD, University of Minnesota, Minneapolis, MN

Barry Rayburn, MD, University of Alabama-Birmingham, Birmingham, AL

Stanton Nolan, MD, University of Virginia (retired), Charlottesville, VA


Data Safety Monitoring Board:

Blasé Carabello, MD, Baylor University VA, Houston, TX,

Robert Bourge, MD, University of Alabama-Birmingham, Birmingham, AL

Robert Emery, MD, Regions Medical Center, St. Paul, MN

Stanton Nolan, MD, University of Virginia (retired), Charlottesville, VA

Chris Lyle, RCRI, Minneapolis, MN

The trial was initiated as a feasibility study in April 2003 and expanded with FDA approval into a pivotal study in June 2004

Role of the funding source

The Sponsor designed the trial in collaboration with the FDA, a scientific advisory board and potential investigators. Data collection was done by each site. After Myocor (the Sponsor) was dissolved, the analysis, writing, and submission was performed by the PI with assistance of the coauthors.



Appendix B. Study Inclusion / Exclusion Criteria

These criteria were selected by the Sponsor in collaboration with the FDA. The philosophy of the study design was to 1) select pure functional MR patients in whom there was enough disease to warrant valvular intervention and 2) select patients whose comorbidities would be associated with sufficient survival to allow assessment of device therapy.


Inclusion Criteria (patients were included if they meet all of the following criteria):

1. Grade 2, 3 or 4 functional mitral valve regurgitation per 2D echocardiography For the purpose of this study, functional mitral valve regurgitation is defined as mitral valve dysfunction due to dilation of the mitral valve annulus, displacement of the left ventricular papillary muscles, chordal tethering of the mitral valve leaflets, or any combination of these characteristics. This was core lab verified.

2. Patient undergoing concomitant coronary artery bypass graft surgery, either on-pump or off-pump (CABG or OP-CAB)

3. Left ventricular ejection fraction > 25% per 2D echocardiography

4. Age between 18 and 80 years, inclusive

5. Patient is willing and available to return for study follow-up

6. Ability of the patient or legal representative to understand and provide signed consent for participating in the study
Exclusion Criteria (patients were be excluded from study participation if they meet any of the following criteria):
1. Structural abnormality of the mitral valve (e.g. calcification or thickening of valve leaflets, ruptured papillary muscle, ruptured chordae tendinae, mitral valve prolapse, mitral stenosis, etc.)

2. Organic valve disease resulting in insufficiency or stenosis of the aortic, pulmonary or tricuspid valve requiring surgical intervention.

3. Transmural myocardial infarction within 30 day period prior to surgical placement of Coapsys.

4. NYHA Class IV

5. Left ventricular end diastolic diameter >7.0 cm

6. Cardiac surgery on an emergency or salvage basis

7. Left atrial or left ventricular thrombus

8. Left ventricular aneurysm

9. Previous mitral valve surgery or other previous cardiac surgery that would preclude proper placement of the Coapsys

10. Chronic renal failure requiring dialysis

11. Open chest surgery contraindication (e.g., acute respiratory distress, endocarditis, myocarditis, pericarditis)

12. Active infection

13. Life expectancy of less than 12 months

14. Participation in another investigational drug or device protocol


Appendix C: Primary Adverse Event (PAE) Definitions

A Primary Adverse Event could occur anytime post randomization, throughout entire patient follow-up.



  1. Death:

    1. Cardiac: Any death originating from an insult to the heart, such as those caused by acute MI, arrhythmia, etc., and deaths of unknown origin.

    2. All-cause: all deaths, including cardiac death.

  2. Stroke: any hemorrhagic or ischemic cerebrovascular event that causes functional loss or impairment lasting equal to or greater than 24 hours or that causes any neurological deficit associated with a positive imaging study, regardless of duration.

  3. Myocardial Infarction:1 One of the following criteria satisfy the diagnosis for an acute, evolving or recent MI

    1. Typical rise and gradual fall (troponin) or more rapid rise and fall (CK-MB) of biochemical markers of myocardial necrosis with at least one of the following:

      1. Ischemic symptoms

      2. Development of pathologic Q waves on the ECG;

      3. ECG changes indicative of ischemia (ST segment elevation or depression); or

      4. Coronary artery intervention (e.g., coronary angioplasty).

    2. Pathologic findings of an acute MI.

Alpert J, Thygesen K, et al. Myocardial Infarction Redefined - A Consensus Document of The Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction. JACC 2000; 36 [3]: 959-69.



  1. Cardiac operation for:

    1. Bleeding: any new surgical procedure to stop or control cardiac bleeding.

    2. Heart valve problems: any new surgical procedure to correct valve malfunctions, replace valves, or correct insults to cardiac tissue resulting from the valve repair.

    3. Life-threatening arrhythmias: any new surgical intervention to treat life-threatening arrhythmias (VT, VF, SVT) including catheter ablation and ICD implantation. The use of IV drugs, catheter ablation or ICD implant for pre-existing arrhythmia, or prophylactic ICD implant (according to MADIT II criteria) are not included in this definition.

  2. Device Failure: any compromise of the physical integrity of the Coapsys or the open-annuloplasty device (ring or band).

Appendix D: Summary of statistical analysis.

Summary of Stratified tests






Log-rank test

p-value (log-rank test)

Hazard ratio of Treatment/Control (95% confidence limits)

Hazard ratio of Gender (female/male) (95% confidence limits)

Overall survival (ITT)

4.30

0.038

0.421 (0.200, 0.886)

1.83 (0.852, 3.92)

Overall survival (AT)

5.41

0.020

0.378 (0.174, 0.824)

1.79 (0.838, 3.80)

Freedom from PAE (ITT)

5.22

0.022

0.461 (0.258, 0.825)

1.80 (0.978, 3.33)

Freedom from PAE (AT)

6.80

0.0091

0.427 (0.236, 0.773)

1.74 (0.953, 3.18)

Freedom from DSMIR (ITT)

5.50

0.019

0.372 (0.185, 0.749)

2.34 (1.16, 4.71)

ITT – Intent to Treat

AT - As Treated

DSMI – Death,Stroke, MI, or Reoperation for Valve dysfunction
Hazard ratios by strata, ITT




CABG_MVRepair

CABG_Alone

Hazard ratio of Treatment/Control (95% confidence limits)

Hazard ratio of Gender (female/male) (95% confidence limits)

Hazard ratio of Treatment/Control (95% confidence limits)

Hazard ratio of Gender (female/male) (95% confidence limits)

Overall survival

0.505 (0.236, 1.08)

1.68 (0.753, 3.73)

NA

6.48 (0.405, 104)

Freedom from PAE

0.461 (0.250, 0.850)

1.69 (0.883, 3.24)

0.465 (0.071, 3.02)

3.24 (0.497, 21.1)

Freedom from DSMIR

0.410 (0.201, 0.835)

2.18 (1.06, 4.49)

NA

6.48 (0.405, 104)

Log-rank tests by strata, ITT






CABG_MVRepair

CABG_Alone




Log-rank

p-value

Log-rank

p-value

Overall survival

2.46

0.12

3.70

0.055

Freedom from PAE

4.95

0.026

0.306

0.58

Freedom from DSMIR

4.26

0.039

2.14

0.14


Appendix E: Deviations from Randomized Assignment.

CABG+Coapsys Assignment Deviations

3 patients after intraoperative randomization had hemodynamic instability and surgeons elected to perform standard reduction annuloplasty on cardiopulmonary bypass.

2 patients had Coapsys placed without impact on MR grade; one patient received reduction annuloplasty and one received mitral replacement.

2 patients after CABG performed had hemodynamic instability during Coapsys procedure; the devices were removed and the patients received no MR treatment.



CABG+MVRepair Assignment Deviations:

2 patients had reduction annuloplasty performed without impact on MR grade and were intraoperatively converted to mitral replacement


Appendix F: Incidence of Primary Adverse Events and ICD implantation During Follow-up.

PAE Event

Control

N= 83


(percent of patients)

Treatment

N = 82


(percent of patients)

Death*

22 (26.5)

11 (13.4)

Stroke

5 (6.0)

3 (3.7)

Myocardial Infarct

5 (6.0)

0 (0)

All Cardiac Reoperation

14 (16.9)

9 (11.0)

Reoperation for Valve Dysfunction

1 (1.2)

2 (2.4)

Device Failure

0 (0)

0 (0)

ICD Implant

8 (9.6)

10(12.1)


* 73% of deaths in each stratum were cardiac related
Appendix G: Summary of NYHA class improvement from baseline in randomized groups - CABG+MVRepair stratum.


Time

Control

Treatment

NYHA class improvement ≥ 1 class

NYHA class improvement ≥ 1 class

Frequency

Proportion

# known

Frequency

Proportion

# known

12 months

29

0.659

44

36

0.706

51

24 months

18

0.720

25

27

0.794

34



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