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a Cardiopulmonary Research Science and Technology Institute, Dallas, Texas
b Duke University Medical Center, Durham, North Carolina
c Duke Clinical Research Institute, Durham, North Carolina
d East Carolina Cardiovascular Institute, Greenville, North Carolina
e PERFUSE Angiographic Core Laboratory, Boston, Massachusetts
f Missouri Baptist Medical Center, St. Louis, Missouri
g Medical City Dallas Hospital, Dallas, Texas
Accepted for publication October 2, 2007.
* Address correspondence to Dr Magee, Medical City Dallas Hospital, 7777 Forest Lane, Ste A323, Dallas, TX 75230 (Email: mmagee{at}csant.com).
Presented at the Fifty-third Annual Meeting of the Southern Thoracic Surgical Association, Tucson, AZ, Nov 8–11, 2006.
| Dr Califf discloses that he has a financial relationship with Corgentech.
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Abstract |
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Methods: The PREVENT IV was a multicenter (107 sites) randomized trial of edifoligide to prevent vein graft failure from neointimal hyperplasia in 3,014 patients undergoing primary, isolated coronary artery bypass grafting (CABG) with at least two vein grafts. One-year angiographic follow-up was completed on 1,920 patients (4,736 grafts) with MACCE follow-up on 99.4% of enrolled patients.
Results: In all, 2,377 procedures (78.9%) were on pump and 637 (21.1%) were off pump. On-pump patients had more chronic lung disease (17% versus 11%; p < 0.001), congestive heart failure (10% versus 7%; p = 0.03), lower mean ejection fraction (50% versus 55%; p < 0.001), and worse target artery quality (good 63.8% versus 68.1%; fair 26.4% versus 22.7%; poor 9.8% versus 9.2%; p < 0.001). Vein graft failure (more than 75% graft stenosis) in on- versus off-pump patients was 25.3% versus 25.7% (p = 0.62). After adjusting for differences in significant predictors of vein graft failure (target artery quality, surgery time, endoscopic vein harvest, more than 1 distal anastomosis/graft, and patient weight), the odds of vein graft failure was 0.82 (95% confidence interval: 0.67 to 1.00; p = 0.05) for on-pump versus off-pump patients. One-year mortality for on- versus off-pump patients was 3.3% versus 2.5% (p = 0.30); and MACCE was 15.4% versus 11.3% (p = 0.01). The adjusted hazard ratio for 1-year MACCE was 1.31 (95% confidence interval: 1.01–1.69; p = 0.01) for on pump versus off pump.
Conclusions: Observed saphenous vein failure rate was 25% in both groups. One-year clinical outcomes (MACCE) were better with off-pump than with on-pump CABG, suggesting benefits not related to vein graft patency.
Coronary artery bypass grafting (CABG) is the most common surgical procedure in the United States, benefiting a large number of patients [1]. According to the latest published statistics from the National Center for Health Statistics, 467,000 CABG procedures were performed in the Untied States in 2003. In high-risk patients, CABG has been shown to decrease mortality over a 10-year study period. Improvements in quality of life and relief of angina are also attributed to successful CABG surgery [2, 3].
Off-pump coronary artery bypass graft surgery (OPCABG) was introduced into routine clinical practice in the mid 1990s in an attempt to decrease the adverse clinical consequences associated with conventional coronary artery bypass. Although the percentage of OPCABG procedures steadily increased to 20% to 25% of all CABG procedures from 1995 through 2002, that adoption rate has leveled off during the ensuing 4 years. According to The Society of Thoracic Surgeons National Clinical Database (STS-NCD), 28,835 of 136,897 CABG operations (21%) performed in 2004 were off pump. Widespread adoption of OPCABG has been limited by controversy regarding the relative benefits of OPCABG compared with conventional on-pump coronary artery bypass. The increased technical demands inherent in the OPCABG procedure have resulted in concern due to the potentially negative impact on graft patency and associated clinical outcomes.
Autologous saphenous vein remains the most frequently used conduit. The long-term patency of vein grafts is limited, and graft failure has consequences similar to those of native coronary artery disease: recurrent angina, myocardial infarction (MI), additional revascularization procedures, and premature death [4, 5]. Long-term angiographic studies of CABG grafts show occlusion rates of 15% to 20% at 1 year, increasing to 40% at 10 years [6, 7].
The PREVENT IV (PRoject of Ex-vivo Vein graft ENgineering via Transfection IV) trial is a multicenter, randomized trial testing the efficacy of edifoligide, an E2F transcription factor decoy, for prevention of vein graft failure due to neointimal hyperplasia after coronary artery bypass graft surgery. All patients had to have two or more vein grafts. After routine harvest, vein grafts were randomly treated with either edifoligide or placebo in a pressurized chamber to achieve transfection of the transcription factor decoy. The decision to perform the bypass graft procedure on pump or off pump was not randomized and was determined by the individual surgeon’s preference. Similarly, the method of vein harvest, endoscopic or open, was not mandated and was left to the discretion of the surgeon. The results of the PREVENT IV trial have been reported elsewhere, and it was found that edifoligide did not have a significant effect on vein graft patency compared with placebo [8, 9].
The PREVENT IV study offers an opportunity to analyze a large patient population undergoing off-pump and on-pump CABG to determine factors influencing 1-year graft patency and major adverse cardiac and cerebral events (MACCE). We sought to determine the influence of off-pump compared with on-pump surgery on graft patency and MACCE, and identify any additional factors influencing outcomes unique to either the off-pump or on-pump technique in patients enrolled in the PREVENT IV trial.
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Material and Methods |
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The method of vein harvest, open or endoscopic, and the surgical technique, on pump or off pump, was not randomized and was left to the discretion of the individual surgeon for each patient procedure. The vein graft quality and target artery quality were subjectively assessed by the surgeon at the time of the procedure and documented on the data collection form along with other intraoperative variables.
This subanalysis is a comparison of patients undergoing on-pump and off-pump CABG to determine (1) the effect of the method of CABG on 1-year angiographic vein and arterial total graft failure, (2) the effect of the method of CABG on the occurrence of major adverse cardiac and cerebral events (MACCE), defined as the composite of death, MI, or stroke at 1 and 2 years after CABG, and (3) the effect of other factors on overall graft patency and to ascertain any factors uniquely related to the method of CABG.
Statistical Methods
The distributions of baseline and graft characteristics are summarized using medians and 25th and 75th percentiles for continuous variables and percentages for categorical variables. Group differences in baseline characteristics, graft characteristics, hospitalization endpoints, and per patient angiographic endpoints were assessed using the Wilcoxon rank-sum test for continuous variables and the 
2 test for categorical variables.
Outcome differences in the MACCE endpoint were assessed using a Cox proportional hazards model. Covariates included in these analyses were age, sex, smoking status (previous or current versus never), history of congestive heart failure, prior atrial fibrillation, and the number of vein grafts implanted. Hazard ratios and 95% confidence intervals were calculated with the Cox model.
To determine predictors of vein graft failure, a logistic regression approach was not appropriate because there were multiple grafts within a patient, and independence between grafts within a patient could not be assumed. Instead a generalized estimating equations (GEE) approach was employed.
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Results |
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Baseline characteristics comparing the on-pump and off-pump groups and the total study population are shown in Table 1. On-pump patients compared with off-pump patients were younger, had more chronic obstructive pulmonary disease, more congestive heart failure, lower ejection fraction, more urgent than elective surgery, and longer operative times. The mean number of bypass grafts was greater in the on-pump group (3.5 versus 3.3), with increased percentages of patients receiving 4 and 5 grafts.
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As vein graft quality deteriorates from good to poor, the graft failure rate increases in both on-pump and off-pump patients, but this effect was significantly greater in the off-pump group: 44.4% of the off-pump patients with poor quality grafts failed compared with 30.6% in the on-pump group.
Clinical Outcomes: Major Adverse Cardiac and Cerebral Events
The MACCE (death, stroke, MI) measured 1 year after CABG was statistically different between on-pump and off-pump groups with 15.4% (367 of 2,377) for the on-pump group and 11.3% (72 of 637) for the off-pump group (p = 0.012). After adjusting for other factors that influence MACCE in this population (age, sex, smoking status, history of congestive heart failure, history of atrial fibrillation, number of grafts implanted), the effect of being on pump versus off pump remained significant (hazard ratio = 1.31, 95% CI: 1.01 to 1.69). There was no difference in reported MACCE between the two groups at 2 years. Need for repeat revascularization was not included in the composite clinical endpoint owing to the occurrence of revascularization based on findings identified at routine 1-year angiography in the absence of other clinical events.
Predictors of Failed Grafts
Several patient and graft characteristics were determined to be significant predictors of graft failure, including the use of cardiopulmonary bypass (p = 0.022). Table 8
shows the results of multivariable analysis used to determine predictors of graft failure. Target artery location was not associated with graft failure. There were significant interactions between cardiopulmonary bypass use and harvest technique, as well as cardiopulmonary bypass use and graft quality. For grafts harvested endoscopically (compared with open), the probability of graft failure was higher if the surgery was performed off pump (odds ratio [OR] = 1.78 for off pump versus 1.27 for on pump). If a poor or fair quality graft was used compared with good, the probably of graft failure was higher if the surgery was performed off pump (OR = 1.90 for off pump versus 1.23 for on pump). For the other characteristics associated with graft failure, the risk of graft failure was similar for on-pump and off-pump surgery.
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Comment |
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The percentage of patients with occlusion of at least one vein graft was the same in off-pump and on-pump surgery (42%). The graft failure rate was similar in on-pump and off-pump surgery, 25.3% versus 25.7% for veins, and 8.0% versus 8.6% for IMAs. Not surprisingly, vein grafts were 2.5 times more likely to fail than IMA grafts, and this was seen equally in both on-pump and off-pump groups. Although it is commonly thought to be technically more challenging in off-pump surgery to graft target vessels on the lateral and inferior walls, the failure rates of grafts to those target vessel locations were similar: approximately 25% in both off-pump and on-pump groups. Grafts to target arteries other than the LAD had a higher failure rate in both on-pump and off-pump patients, likely reflecting the LAD as a better target vessel and the common use of the left IMA to graft the LAD.
Poor target artery quality is associated with increased graft failure at 1 year, in both on-pump and off-pump patients (OR = 2.38). Poor vein graft quality is associated with increased graft failure rates in all patients, but impacted off-pump patients (OR = 1.89) significantly more than on-pump patients (OR = 1.09). Endoscopic vein harvest is also associated with graft failure in all patients but again affected off-pump patients significantly more (OR = 1.78) than on-pump patients (OR = 1.27).
Major adverse cardiac and cerebral events (death, MI, and stroke) at 1 year is 33% more likely if surgery is on-pump. This benefit of decreased MACCE associated with off-pump surgery at 1 year is no longer present 2 years after CABG. Other patient factors including progression or development of comorbid disease or progression of coronary artery disease likely affects MACCE to a greater degree than the surgical technique 2 years after CABG.
This subanalysis of the PREVENT IV data is both confirmatory and enlightening regarding known or suspected factors influencing graft failure in a current population of patients undergoing off-pump and on-pump CABG. More patients currently referred for CABG have diffuse multivessel coronary artery disease with one or more poor quality target vessels that are often combined with poor vein graft quality or limited good vein graft quality. These same patients frequently have comorbidities that put them at increased risk for perioperative morbidity and mortality. Such high-risk patients have previously been shown to benefit most from off-pump surgery [10]. Endoscopic vein harvest has been used increasingly in the past 4 years owing to increased patient satisfaction with this less invasive approach and decreased lower extremity wound complications compared with the open technique [11]. Previous studies have shown that endoscopic vein harvest is safe and does not affect 6-month patency rates [12]. The relative hypercoagulable state that occurs with off-pump surgery combined with intraoperative conditions that predispose to endothelial injury, including those affecting the vein and target vessels, may account for the increased graft failure rates seen in off-pump patients with poor quality vein harvested endoscopically placed to poor quality target vessels. Cardiac surgeons may often encounter a high risk patient who would benefit from off-pump surgery in whom vein has been harvested endoscopically and subsequently judged to be fair or poor quality along with one or more poor target vessels to bypass. The risk of placing such a patient on cardiopulmonary bypass and the associated increased risk of death, MI, or stroke must be weighed against the increased risk of graft failure up to 1 year after CABG associated with off-pump surgery.
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Discussion |
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TopAbstractIntroductionMaterial and MethodsResultsCommentDiscussionReferences |
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DR MAGEE: Thank you, John, for your comments and questions. I will try to remember all of those. I think I may have missed your first question. The second question regarding why this overall incidence of graft failure was high, the reason for that is the fact that the follow-up is excellent in this analysis; there was a large number of patients analyzed. And it accurately reflects current practice in that target artery qualities in patients are more difficult to operate on in this era, and I think that our graft quality and our target artery quality is indeed poorer and that is having a significant effect, as was shown in this study, on graft failure. And I think this truly does reflect the current graft failure rate in this patient population. Could you tell me again what the first question was?
DR PUSKAS: The first question, Mitch, was about the MACCE. You saw a 33% reduction in MACCE in the OPCABG group initially, but that benefit seemed to vanish by 2 years’ follow-up.
DR MAGEE: I can only suspect that the main benefits of off-pump surgery are primarily in the perioperative period and that perhaps between 1 year and 2 years other patient factors, either progression of comorbid disease or development of comorbid disease, has an effect on MACCE at that point as much as progression of coronary artery disease that may offset that benefit that you see in the early perioperative period.
DR PUSKAS: That makes sense.
DR MAGEE: In terms of why I think this has more of an effect on off-pump surgery, all of the factors that impacted graft failure rates, poor target artery quality, poor conduit quality, endoscopic vein harvest, are all things that may potentially aggravate endothelial injury, and in patients who are done off pump, there is a propensity I think for those patients to have a hypercoagulable condition, as you suggest, and I think that systemic condition in conjunction with these other factors that are shown to affect graft patency combine to make that condition less favorable in the off-pump patient compared with the on-pump patient.
In terms of how we may manage our practice in the future, certainly in a patient who has poor vein graft quality, endoscopically harvested, and multiple targets that are also perceived to be poor quality and that patient does not have other factors that would tend to sway me toward doing that patient off pump, I would have a lower threshold for putting that patient on pump.
DR PUSKAS: And you are doing that because you think that you will have favorable coagulopathy or because you think you can construct your anastomoses more precisely?
DR MAGEE: I think it is more of a systemic problem rather than a technical one, and I think the fact that the grafts laterally and inferiorly, which are often perceived to be technically more challenging in the off-pump patients, (the graft failure rate was no different in off-pump versus on-pump group), favors that conclusion that in fact, technically, it is not a more difficult operation.
DR PUSKAS: I would agree. Are you giving Plavix in the immediate postoperative period?
DR MAGEE: We have loaded the patients immediately after surgery with Plavix and have maintained them for 3 months on Plavix in our practice.
DR PUSKAS: We have a similar protocol. We give 150 mg of Plavix in the recovery room as soon as it is clear that patient is not bleeding, and then they get 75 a day for 3 months.
DR MAGEE: I think one of the more concerning things is this endoscopic vein harvest decrease in graft patency associated with that, and this certainly has heightened our concern.
DR PUSKAS: We have noticed occasionally a little string of fibrin within an endoscopically harvested conduit, and that has prompted us to give about 2,000 units of heparin at the beginning of the case.
DR MAGEE: We have had the same experience and have managed it similarly.
DR THORALF SUNDT (Rochester, MN): I have the same concern about endoscopic harvest. With regard to graft patency, I think we have a problem, ladies and gentlemen. The cardiologists have seen these data, and at the most recent cardiology board review course that was run in Rochester with many cardiologists in attendance getting ready to take their boards, these statistics were put up over and over and over again. I don’t think we have any right to whine about subacute thrombosis of drug-eluting stents when we are doing an operation with a 25% graft occlusion rate. And I am particularly concerned as we have adopted less invasive techniques such as endoscopic harvesting, if we are doing things that are promoting that decline in graft patency. If so, then we are shooting ourselves in the foot. We ought to pay attention to graft patency and to what Rick Barner has been saying since the 1970s and use arterial grafts instead of venous grafts whenever possible.
DR MAGEE: I think your point is well taken. I do want to point out the fact, though, that despite the graft failure rate being moderately high, the MACCE rate was lower. What was shown in the main PREVENT IV trial was that there were more than half of the patients who had vein graft failure who did not have a MACCE event. So vein graft failure does not necessarily translate into a poor outcome.
DR SUNDT: That starts to sound more and more like the cardiologists that are saying, yeah, there is restenosis but it is not a problem. I just assure you the cardiologists have noticed this graft occlusion rate. That is only the comment I want to make.
DR MAGEE: I think that does need to be addressed.
DR ROBERT A. GUYTON (Atlanta, GA): I think that we need to take ownership of this issue and this problem, and I really feel that we need to think about every surgeon doing 20 postoperative catheterizations per year at the beginning of the year, you have got to be able to prove that you can have a 95% discharge patency with mammaries and a 92%-plus patency with vein grafts. I agree with Thor. We have got to take ownership of this problem, and to attempt to say this is not an issue and not a problem is the wrong approach to take by our Society.
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75% Stenosis) Assessed by Follow-Up Angiogram
a