Saphenous Vein Grafts with Multiple Versus Single Distal Targets in Patients Undergoing Coronary Artery Bypass Surgery: One-Year Graft Failure and Five-Year Outcomes from the Project of Ex-vivo Vein Graft Engineering via Transfection (PREVENT)-IV Trial Rajendra H. Mehta, MD, MS; T. Bruce Ferguson, MD; Renato D. Lopes, MD, PHD; Gail E. Hafley, MS; Michael J. Mack, MD; Nicholas T. Kouchoukos, MD; C. Michael Gibson, MD; Robert A. Harrington, MD; Robert M. Califf, MD; T. Bruce Ferguson, MD; Eric D. Peterson, MD, MPH; John A. Alexander, MD, MS; on behalf of PREVENT-IV Investigators

Disclosures Rajendra H Mehta-None, T. Bruce Ferguson-None, Renato D. Lopes-None; Gail E. Hafley, MS-None, Michael J. Mack, MD-None, Nicholas T. Kouchoukos-None, C. Michael Gibson-None, Robert A. Harrington-Research Grants From Corgentech and Bristol-Myers Squibb, Eric D. Peterson- Research Grants from Merck/Schering Plough, Bristol- Myers Squibb and Society of Thoracic Surgery, Robert M. Califf-None, John A. Alexander-None. The PREVENT IV Trial was supported by Corgentech and Bristol-Myers Squibb

Background Saphenous vein grafts (SVG) with single proximal and multiple distal anastomosis (m-SVG) are often used during CABG Advantages of m-SVG versus multiple single SVG (single proximal and distal anastomosis, s-SVG) include Shorter vein segment allowing bypasses of >1 vessel Shorter revascularization time because of single proximal anastomosis Used by many in emergent/salvage/urgent situation and when inadequate vein conduits available for bypass. Most studies evaluating outcomes of m-SVG versus s-SVG Single center No systematic angiographic follow-up Preceded the era of improved medical therapy

Objectives Hypothesis To assess the patency of m-SVG compared with s-SVG in patients undergoing CABG To assess the influence of m-SVG use on the short- and long-term (5-year) clinical outcomes in patients undergoing CABG Hypothesis The use of m-SVG and s-SVG will have similar 1-year vein graft patency and 5-year clinical outcomes in patients undergoing CABG

Study Design & Follow-Up Enrolled Patients (n=3014) EDIFOLIGIDE (n=1508) PLACEBO (n=1506) Angiography Cohort (n=1197) Non-Angiography (n=311) Angiography Cohort (n=1203) Non-Angiography (n=303) 1-year Angiographic Endpoint (81%) 1-Year Angiographic Endpoint (79%) 5-Year Clinical Endpoint (99.7%) 5-Year Clinical Endpoint (99.2%)

Inclusion / Exclusion Criteria First CABG Age 18–80 years At least 2 planned autogenous vein grafts Informed Consent (including angio f/u) Exclusion Prior CABG or valve surgery Planned concomitant valve surgery Vasculitis or hypercoaguable state Comorbidity making 5-year survival unlikely Enrollment in another trial w/ Edifoligide or another investigational drug or device

Methods Patient Population and Definitions All patients enrolled in the PREVENT-IV trial M-SVG = graft with 1 proximal and >1 distal anastomosis SVG failure was defined as stenosis >75% of at least 1 SVG on follow-up quantitative angiography Failure of any part of a m-SVG was defined as graft failure

Methods Statistical analyses Covariate adjusted analyses of outcomes (death, MI, revascularization, vein graft failure) were assessed using a Cox proportional hazards model. Covariates included age, gender, history of congestive heart failure, recent myocardial infarction (within 30 days), status of operation, harvesting technique and use of IMA conduit and CPB. For per graft endpoints, general estimating equation techniques were used to adjust for correlation between grafts within a patient. Covariates included weight, duration of surgery, CPB use, harvest technique, target artery quality, vein graft quality and whether graft was a m-SVG or not.

Results

Results Clinical Characteristics Characteristics Overall (n=3014) No m-SVG (n=1969) m-SVG (n=1045) P value Age, median (IQR), years 64 (56, 71) 63 (56, 70) 0.416 Female sex 20.9% 22.8% 17.3% <0.001 Race-nonwhite 9.1% 0.285 Medical history Hypertension 75.1% 74.4% 76.5% 0.20 Diabetes Mellitus 37.8% 36.9% 39.4% 0.18 Current Smoking 22.9% 23.0% 22.7% 0.17 Chronic Lung Disease 15.8% 15.6% 16.1% 0.73 Preoperative A Fibrillation 7.0% 6.6% 7.8% Myocardial Infarction 42.2% 42.4% 0.90 Renal insufficiency (GFR<60) 2.2% 2.1% Congestive Heart Failure 9.7% 9.5% 10.0% 0.72 Prior stroke 5.5% 5.8% 4.9% 0.30 Peripheral Vascular Disease 12.2% 12.0% 12.6%

Results: Presenting features Overall No m-SVG M-SVG P Heart rate (median [IQR]), bpm 70 (62, 80) 71 (62, 80) 0.222 SBP (median [IQR]), mmHg 134 (120, 149) 133 (120, 149) 134 (120, 150) 0.276 DBP (median [IQR]), mmHg 75 (67, 82) 76 (66, 82) 74 (68, 82) 0.029 Peoperative NYHA Class 0.374 I 40.2% 40.7% 37.3% II 33.4% 33.3% 33.8% III 18.0% 17.9% 18.8% IV 8.4% 8.1% 10.2% LVEF, median (IQR) 50% (40%, 60%) 50% (42%, 60%) 0.018 No of Diseased Vessels >2 or left main (>75% Stenosis) 79.4% 78.3% 81.6% 0.031 Reformat Are you sure this is worth including. Number of diseased vessels is the only interesting finding.

Results: Surgical Characteristics Characteristics Overall No m-SVG P value IMA Graft 92.5% 95.7% 89.9% <0.001 Surgery Duration, median (IQR), min 231 (193, 272) 226 (190, 267) 237 (201, 280) Cardiopulmonary Bypass 78.9% 74.7% 86.8% Duration of Cardiopulmonary Bypass, median (IQR), min 100 (79, 123) 97 (77, 121) 104 (82, 127) Postoperative Duration, median (IQR) Ventilator, hrs 8 (5, 14) 7 (5, 13) 0.025 ICU stay, hrs 26 (22, 47) 26 (22, 48) 0.674 Hospital Stay, days 6 (5, 8) 0.524 Poor Target Artery Quality 21.2% 21.9% 19.6% 0.296 Reformat

Vein Graft Failure (≥ 75%) HR 1.24, 95% CI 1.03-1.48 HR 1.40, 95% CI 1.13-1.76 Do you need this? m-SVG no m-SVG m-SVG No m-SVG

SVG Failure rates in Various Groups Reformat. would remake the figure in powerpoint. Its easy to do and will look better. There is a typo in “Both “SBG”-F”. This will take some work to explain. Key is that it is per-patient SVG failure.

5- Year Major Adverse Clinical Events (m-SVG vs. s-SVG [referent])

5- Year MACE in Angiographic Cohort Includes Perioperative MIs I would redraw this figure in powerpoint. I might be clearer if switched bar 2 and 3. This will take some explaining.

5- Year MACE in Angiographic Cohort Excluding Perioperative MIs Results are the same w or w/o peri-op MI. I would only show 1. Probably w/o peri-op MI.

4- Year MACE (Death/MI/Revasc) Rates in Angiographic Cohort (Excluding All Events Before Angiogram). Results are the same w or w/o peri-op MI. I would only show 1. Probably w/o peri-op MI.

Strengths Limitations First study to prospectively collect not only clinical but also angiographic data. Limitations Non-randomized, retrospective analysis of the PREVENT IV data limiting inference regarding causation. Small number of patients with isolated m-SVGs or m-arterial grafts (consistent with contemporary practice). No differentiation possible between ‘Y’ vs. ‘Sequential’ anastomosis of m-SVG. Only patients undergoing first CABG in PREVENT-IV

Conclusions The use of m-SVG conduits was associated with a higher rate of vein graft failure and worse 5-years outcomes. The worse outcomes associated with m-SVG appeared to be related to the worse outcomes associated with any SVG failure, thus higher m-SVG failure rates translated into poorer outcomes for patients who received m-SVGs. This data should stimulate the use of s-SVG over m-SVG when feasible. Additional studies are needed to identify the most appropriate conduit and strategies to improve long-term graft patency of both m- and s- SVG as well as for improving the overall clinical outcomes in patients undergoing CABG.