Abstract: Saphenous vein grafts are prone to degeneration and occlusion. Vein graft disease continues to be a significant problem in maintaining long-term benefits after coronary artery bypass surgery. The neointimal hyperplasia and aggressive atherosclerosis that occur in saphenous vein grafts make interventions particularly challenging due to plaque embolization and the no-reflow phenomenon. This review discusses the pathophysiology of vein graft disease and the various percutaneous strategies that have been applied to manage vein grafts. We review the issues surrounding stent selection and various approaches to embolic protection devices. Finally, we discuss the technical steps that optimize success in treating this challenging patient subset.
Key words: embolic protection devices, saphenous vein grafts, plaque embolization, no-reflow
Degeneration and occlusion of saphenous vein grafts (SVG) continue to be significant problems in maintaining long-term benefit in patients who have undergone coronary artery bypass graft (CABG) surgery. SVG occlusion during the first year is high at 15%, and 10-year patency is only 60%.1-4 SVG failure is associated with a significant increase in major adverse cardiovascular events (MACE), including death, myocardial infarction (MI), and the need for repeat revascularization.5 Predictors of vein graft occlusion include tobacco use, hypertension, dyslipidemia, and small target vessel diameter (<2 mm).6 SVG percutaneous coronary intervention (PCI) comprises an important subset of interventions in the cardiac catheterization laboratory. According to the American College of Cardiology National Cardiovascular Data Registry, there were over 90,000 patients (5.7% of all PCIs) who underwent SVG PCI between 2004 and 2009.8
SVG disease occurs in 3 phases: early (before hospital discharge); intermediate (1 month to 1 year); and late (beyond 1 year). Early graft failure is due to thrombotic closure, usually at the site of anastomosis, as a result of endothelial injury and the release of inflammatory cytokines during surgery. Technical factors, such as poor distal runoff, graft kinking, and small target vessel diameter, predispose grafts to early occlusion.6,7 After the first month, exposure of the vein grafts to arterial pressure results in neointimal hyperplasia. This pathophysiologic process causes intimal damage, fibrosis, platelet aggregation, the release of growth factors, and smooth muscle cell proliferation.6 After the first year, aggressive atherosclerotic narrowing occurring over the already abnormal endothelium is the main mechanism for graft failure.
Atherosclerotic plaques in SVGs are more diffuse, friable, contain more foam and inflammatory cells, have absent or small fibrous caps, and little or no calcification in comparison to native coronary atherosclerosis.6 These characteristics predispose SVGs to extensive thrombotic burden and distal embolization during coronary graft interventions, resulting in the no-reflow phenomenon, and hence, more periprocedural MI. Grafts particularly susceptible to these effects are those of an older age with more ectasia and greater plaque burden.9
Various strategies have been applied in the treatment of patients with SVG failure. Redo-CABG surgery is associated with a marked increase in morbidity and mortality compared with initial surgery10-12 and is therefore used as a last resort. Percutaneous transluminal coronary angioplasty (PTCA) alone also proved to be inadequate therapy with unacceptably high rates of restenosis and MACE.13-15
The Saphenous Vein De Novo (SAVED) trial was the seminal study that compared balloon angioplasty with bare-metal stents (BMS) in SVG lesions.16 This demonstrated that the use of BMS had a better composite outcome of freedom from death, MI, repeat CABG, and target lesion revascularization (TLR).
The advent of drug-eluting stents (DES) dramatically reduced restenosis in native coronaries. With the high rates of restenosis in SVGs,17 DES were also applied in the treatment of SVG stenosis.
Some observational studies comparing DES to BMS in SVG PCI suggest that DES was associated with reduction in TLR and death.18-21 Other studies, however, showed no difference between DES and BMS in terms of death, MI, and target vessel revascularization (TVR).22-25
Randomized prospective studies comparing BMS to DES in SVG PCI are less conclusive because of the small number of studies available and their small sample size. The Reduction in Restenosis in Saphenous Vein Grafts with Cypher (RRISC) trial and the Stenting of Saphenous Vein Graft (SOS) trial compared DES to BMS and found a significant reduction in restenosis and TLR, but no difference in mortality.26,28 RRISC also found a reduction in TVR. However, at 3-year follow-up from the RRISC trial (DELAYED RRISC), there were more deaths in the DES compared with the BMS group.27 In addition, the decrease in TVR seen at 6 months was not noted at follow-up. In contrast, a 3-year follow-up from the SOS trial demonstrated continued benefit with DES, with lower rates of MI and target vessel failure as well as a trend toward less stent thrombosis.29 There were no differences in all-cause mortality or cardiac mortality. Recent meta-analyses have shown that DES had lower TVR and TLR in the observational studies, but this was not confirmed in the randomized studies.30-35
The moderate VEin graft LEsion stenting with the Taxus stent and Intravascular ultrasound (VELETI) trial poses an interesting consideration in the future management of SVG disease. This study showed that stenting moderate SVG lesions with DES showed better luminal area, no progression to occlusion, and a trend toward lower incidence of MACE compared to medical treatment alone.36 A 3-year follow-up confirmed that the incidence of MACE was significantly lower in the stented group.37 Further studies are required to determine if this preventive approach leads to long-term benefit.
Pharmacologic and Mechanical Strategies to Minimize Complications During SVG PCI
The increased incidence of plaque embolization and platelet aggregation presents unique and significant procedural challenges during SVG intervention.38,39 Plaques that develop in SVG are friable and bulky, making them technically difficult during interventions. Vein grafts also have no side branches, and plaque embolization often leads to “slow-flow” or “no-reflow” phenomena where there is diminished or loss of antegrade blood flow to the distal vasculature without angiographic evidence of obstruction. The exact mechanism of the no-reflow phenomenon is unclear, but it is thought to be associated with endothelial swelling, neutrophil infiltration, and platelet aggregation causing obstruction and spasm in the microvasculature.40,41
Various pharmacological and mechanical strategies have been developed in an attempt to decrease complications in SVG PCI. Some of the pharmacologic strategies that have been utilized include the use of glycoprotein (GP) IIb/IIIa inhibitors and vasodilators.
GP IIb/IIIa inhibitors. Adjunctive treatment with platelet GP IIb/IIIa inhibitors in primary PCI for acute ST-elevation myocardial infarction (STEMI) has been shown to improve epicardial blood flow and microvascular perfusion, along with decreasing mortality.42,43 However, the same benefits with GP IIb/IIIa inhibitors were not observed in SVG interventions. One of the reasons for this might include the sheer excessive atheroembolic and thrombotic burden present during SVG interventions. No clinical benefit in terms of reduction in MACE was seen in 2 retrospective studies44,45 and a pooled analysis of 5 studies.46 While the Evaluation of IIb/IIa platelet receptor antagonist 7E3 in Preventing Ischemic Complication (EPIC) trial did find a reduction in the rate of distal embolization and a trend toward reduction in early large non-Q wave MI in patients treated with GP IIb/IIIa inhibitors, the 30-day and 6-month clinical endpoints were similar in both groups.47 A post hoc analysis of the FilterWire EX Randomized Evaluation (FIRE) trial77 showed that GP IIb/IIIa inhibitors in conjunction with FilterWire embolic protection device had better outcomes, with better flow through the filter, and reduced procedural ischemia, as well as less abrupt closure, no reflow, or distal embolization.48 However, similar results were not seen with GP IIb/IIIa inhibitors and the PercuSurge GuardWire embolic protection system in the Saphenous Vein Graft Angioplasty Free of Emboli Randomized (SAFER) trial.75 In fact, in this trial, the patients who were preselected to receive GP IIb/IIIa inhibitors had a higher incidence of MACE. The reason for this increased incidence of MACE may partly be due to selection bias, as operators gave GP IIb/IIIa inhibitors to higher-risk patients who had the most unfavorable lesion morphologies. To date, there are no prospective randomized trials clearly demonstrating the benefits of GP IIb/IIIa inhibitors in SVG PCI. However, while GP IIb/IIIa inhibitors have not been shown to reduce mortality or myonecrosis in SVG PCI, there may be a role in their usage as adjuncts with certain embolic protection devices, such as the distal filtration devices.
Vasodilators. Vasodilators that have been studied in the no-reflow phenomenon include adenosine, verapamil, and nicardipine. Adenosine is a very short-acting, endogenous nucleoside that vasodilates arteries and arterioles and prevents platelet aggregation and thrombus formation. Pretreatment with intracoronary adenosine has been shown to decrease the incidence of MI after elective PCI.49,50 Intracoronary adenosine has also been studied in acute MI and was found to improve myocardial flow51,52 and lower the incidence of the no-reflow phenomenon51,53 and reduce CK elevation.51 The Acute Myocardial Infarction Study of Adenosine (AMISTAD) trials showed adjunctive adenosine infusion reduced the infarct size in patients with anterior ST-elevation MI.54,55
Although there are some data showing benefits of adenosine in elective PCI and acute MI, there are only limited data on the use of adenosine in SVG PCI. There are no studies confirming that adenosine prevents no-reflow, but there are a few small studies showing that adenosine aids in reversing the no-reflow phenomenon. Fischell et al showed promising results with adenosine in reversing slow-flow and no-reflow phenomenon among patients undergoing SVG PCI.56 This finding was later confirmed when repeated boluses of high-dose adenosine reversed no-reflow and improved final Thrombolysis In Myocardial Infarction (TIMI) flow grade.57
Calcium-channel blockers also have been shown to help no-reflow in both laboratory animal models58,59 and clinical trials.60-62 One randomized study, the Vasodilator Prevention of No-Reflow (VAPOR) trial, showed that there was a significant reduction in no-reflow and a trend toward improvement in TIMI flow grade with prophylactic intragraft administration of verapamil during SVG PCI.63 However, this was a small study involving only 22 patients. Two other studies showed that intragraft verapamil successfully treated no-reflow in SVG interventions.64,65 Although verapamil aids in no-reflow, there is no evidence that it protects against MI.66
Nicardipine is another potent calcium-channel blocker that has been shown to be effective in aiding no-reflow. Fugit et al compared 3 intracoronary vasodilators (nicardipine, diltiazem, and verapamil) on nonsignificant native coronary artery disease and found that nicardipine was the most potent coronary vasodilator with the fewest systemic side effects.61 In a retrospective study, nicardipine was successful in reversing 98% of no-reflow episodes without any hemodynamic compromise.67 Following this, Fischell et al showed promising results with nicardipine to prevent no-reflow in SVG PCI.68 They found that pretreatment with intragraft nicardipine, even without the use of mechanical embolic protection, resulted in low incidence of no-reflow and in-hospital MACE.68 Although this study did not have a control group available for direct comparison, nicardipine appeared to be clinically beneficial compared to historical control data66,69 where SVG PCI was done without nicardipine or embolic protection device. Given the ease of administration and cost-effectiveness of nicardipine, the authors concluded that nicardipine might be an alternative or adjunct to mechanical protection devices in SVG PCI.68
Although the available data are limited and not enough to support the routine use of adjunctive pharmacotherapy in SVG PCI, the above studies are promising. Currently, aspirin, thienopyridine, and anticoagulation with heparin are the only recommended adjuvant pharmacotherapy in SVG interventions.
Covered stents were developed as a mechanical strategy to serve as a local filter, trapping plaque against the graft wall to prevent the shower of emboli during stent deployment. In addition, it was hypothesized that neointimal proliferation and the ensuing restenosis would be reduced. Favorable results were initially suggested by a multicenter registry,70 but randomized trials failed to show any superiority over BMS.71-73 The Stents IN Grafts (STING) trial showed that death, MI, and TLR were comparable in the polytetrafluoroethylene (PTFE)-membrane covered stents versus conventional stents.71 The Randomized Evaluation of polytetrafluoroethylene COVERed stent in Saphenous vein grafts (RECOVERS) trial also demonstrated similar restenosis rates and clinical outcomes between PTFE-covered stents and BMS with higher incidence of nonfatal MI in the PTFE-covered stent group.72 The Symbiot III trial further confirmed that there was no advantage of the Symbiot PTFE-covered stent over BMS in terms of restenosis rates and clinical outcomes.73 The more recent Barrier Approach to Restenosis: Restrict Intima to Curtail ADverse Events (BARRICADE) trial in fact demonstrated more target vessel failure in patients treated with covered stents compared to BMS.74
Embolic Protection Devices
Mechanical embolic protection devices (EPD) were developed and proved to be the first treatment modality to reduce MACE during SVG PCI. Currently, there are 3 types of EPDs: the distal balloon occlusion/aspiration system; distal filter system; and the proximal occlusion/aspiration system.
Distal occlusion/aspiration system. The PercuSurge GuardWire system occludes the target vessel several centimeters distal to the target lesion during SVG PCI in order to provide myocardial protection. After the intervention, aspiration removes debris-laden blood prior to balloon deflation and restoration of antegrade blood flow (Figure 1).
This was the first EPD to gain Food and Drug Administration (FDA) approval following the results of the Saphenous Vein Graft Angioplasty Free of Emboli Randomized (SAFER) trial.75 This pivotal study showed a remarkable 42% reduction in 30-day MACE and a marked decrease in the no-reflow phenomenon with utilization of EPD.
Following the SAFER trial, the TriActiv system was approved by the FDA after proving its noninferiority in the Protection During Saphenous Vein Graft Intervention to Prevent Distal Embolization (PRIDE) trial.76
Distal filtration system. The FilterWire EX Randomized Evaluation (FIRE) study showed noninferiority of the FilterWire EX System to the GuardWire balloon occlusion and aspiration system and led to FDA approval of the first distal filtration device.77 The FilterWire EX is a guidewire filtration system that uses an oval windsock-shaped filter membrane that is delivered to a “landing zone” distal to the target lesion and then deployed prior to lesion intervention. The intervention is then performed over the wire and a sheath is advanced to retrieve the wire and the filter (Figure 2).
A newer generation of filter devices has since been developed. The Embolic Protection Transluminally with the FilterWire EZ Device in Saphenous Vein Grafts (BLAZE I and II) study showed a decrease in MACE with FilterWire EZ, a second generation of the FilterWire EX78 and the Saphenous Vein Graft protection In a Distal Embolic Protection Randomized Trial (SPIDER) study showed noninferiority of the Spider Rx filtration device to GuardWire and FilterWire.79 The Assessment of the Medtronic AVE Interceptor Saphenous Vein Graft Filter System (AMEthyst) trial examined another filter, the Interceptor PLUS, which was shown to be noninferior to the GuardWire and FilterWire EZ.80
Proximal occlusion/aspiration system. Proximal occlusion devices occlude the vessel proximal to a target lesion and suspend antegrade flow. As with distal occlusion devices, the stagnant blood and debris are then aspirated. The only FDA-approved proximal occlusion/flow reversal device is the Proxis system (Figure 3). This was based on the Proximal Protection During Saphenous Vein Graft Intervention Using the Proxis Embolic Protection System (PROXIMAL) trial that showed the Proxis system to be noninferior to distal EPD.81
The American College of Cardiology guidelines give a class I recommendation for the use of EPD in SVG PCI whenever feasible.82 Despite this, registry data show that EPDs are only utilized in 22% of SVG PCI.83 This may be due to anatomic difficulties, such as challenging take-off from the aorta, very large vessel diameter, and the absence of an adequate non-diseased landing zone. EPD use may also be limited due to the higher procedural cost, longer procedural time, and greater radiation exposure.83 The advantages and disadvantages of each type of EPD are summarized in Table 1.
Practical Approaches to SVG PCI
SVG angiography should be undertaken with knowledge of the operative report and any prior angiograms. It is necessary to know the number, location, and anatomy of grafts. This reduces contrast load, radiation exposure, and vascular complications that may occur when blindly searching for graft ostia. Appropriate catheter selection for angiography can also reduce complications and procedural time.
Recently, noninvasive coronary angiography with multidetector computed tomographic (MDCT) angiography has shown promising results. Saphenous vein grafts are great targets for visualization with MDCT because they have large lumens (4 to 6 mm) and reduced overall motion.84 They also can help define vein and arterial graft anatomy. A study by Schlosser et al showed that MDCT had a sensitivity of 96% and a specificity of 95% in evaluation of graft patency.85 MDCT is limited, however, in the visualization of distal anastomosis sites and segments with adjacent clips. Invasive coronary angiography still remains the gold standard for visualization, diagnosis, and treatment of SVG disease.
Figure 4 illustrates the usual arrangement of vein grafts and the optimal guide catheter selection. The position and angle of graft take-off combined with the size of the aorta determines the type and width of catheter that is appropriate for easy engagement. A vein graft to the right coronary artery often can be engaged by using the Multipurpose catheter, especially if there is a steep inferior take-off. Alternatively, a Judkins Right (JR) catheter or an Amplatz Left (AL) catheter may be used.
Grafts to the left coronary artery can also be engaged by JR catheter, especially if they have a horizontal take-off from the aorta. Alternate catheters include the Left Bypass catheter and the Hockey Stick catheter. Superiorly directed grafts may require an Internal Mammary Artery catheter or an AL catheter.
Once SVG disease is diagnosed and an intervention is required, PCI of the bypassed native vessel should always be considered whenever feasible, as complications of native PCI are lower than that of SVG PCI. If SVG PCI cannot be avoided, the importance of adequate guide support cannot be overemphasized, since safe delivery and retrieval of EPDs need to be taken into account.
Given the current guidelines regarding EPD use,82 we recommend that every effort should be made to use EPDs in SVG interventions whenever technically feasible. The location of the stenosis determines the type of EPD that may be utilized; ostial lesions require a distal EPD, lesions in the body of the graft can be served either by a proximal or distal device, and distal lesions can only be proximally protected. As discussed previously, the addition of intragraft vasodilators should also be considered to aid in the prevention or treatment of no-reflow phenomenon.
The EPD is carefully placed in a satisfactory position. Severe stenoses require predilation with a small balloon. The stent is sized one to one, and high-pressure inflation is avoided to prevent a “cheesegrater effect,” which can increase risk of distal embolization. Minimizing post-stent manipulation is also important to prevent embolization. Both balloon and stent must be well enough away from the EPD to avoid entanglement. Angiography is then repeated to assess the lesion itself and the flow rates in both the vein grafts and the coronary arteries. The myocardial blush grade is also carefully assessed. Slow flow may indicate a packed filter, which should be aspirated and removed. If there is a good angiographic result, the protection balloon is deflated or the filter retrieved. This is a critical step requiring coaxial alignment of the guide to prevent filter entrapment in the stent. A final angiogram is performed to assess the results of the intervention, including the presence of myocardial blush and angiographic flow down the vessel.
SVG PCI is a potentially risk-prone procedure associated with a poor long-term prognosis. Pan-arterial revascularization procedures or a hybrid native coronary stenting with arterial revascularization should be considered to minimize the need for vein grafts.
However, because the use of SVGs is often unavoidable, strict risk factor modifications are important in preventing SVG stenosis. Early aspirin therapy after CABG has improved outcomes including reduction of SVG stenosis and death87,88 and aggressive lipid therapy has also been shown to reduce progression of atherosclerosis in post-CABG patients.89,90 When diseased SVGs require intervention, extreme care must be given in the selection of the stent and the EPD, along with application of good procedural techniques to minimize complications.
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From the Department of Cardiovascular Medicine, Hahnemann University Hospital, Philadelphia, Pennsylvania.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted September 15, 2011, provisional acceptance given October 11, 2011, final version accepted November 15, 2011.
Address for correspondence: Sheldon Goldberg, MD, Hahnemann University Hospital, Broad & Vine Streets, 7th Floor South Tower, Philadelphia, PA 19102. Email: email@example.com