**5. Bare metal stents in the treatment of saphenous vein grafts**

Given the limitations of balloon angioplasty for the treatment of saphenous vein graft disease stent implantation was suggested as an alternative therapeutic approach.

Initial observational studies with balloon-expandable stent implantation in saphenous vein graft lesions had claimed a high procedural success rate, low early complication rate, and more favourable long-term outcome than previously reported for balloon angioplasty alone (Hanekamp et al., 2003).

The SAVED (Saphenous Vein De Novo) trial was the first multicentre, prospective, randomized trial of saphenous vein graft stenting. This study compared the placement of Palmaz-Schatz stents (Johnson & Johnson Interventional Systems, Warren, N.J.) with standard balloon angioplasty in 220 patients with relatively focal de-novo lesions in aortocoronary-venous bypass grafts. The primary angiographic end point of this trial was restenosis, defined as stenosis of 50% or more of the luminal diameter at follow-up.

Patients assigned to stenting had a higher rate of procedural efficacy, defined as a reduction in stenosis to less than 50% of the vessel diameter without a major cardiac complication (92% versus 69%, P<0.001). Bleeding and vascular complications were significantly more common in the stent group (17 % versus 5%, P<0.01) probably related to the intense anticoagulation protocol used in this trial. Patients in the stent group had a larger mean increase in luminal diameter immediately after the procedure (1.92 ± 0.3 mm versus 1.21 ± 0.37 mm) and a greater mean net gain in luminal diameter at six months (0.85 ± 0.96 mm versus 0.54 ± 0.91 mm). The rate of event free survival (freedom from death, myocardial infarction, repeated bypass surgery and revascularisation of the target lesion) at 240 days was significantly greater for patients assigned to stenting than for patients assigned to balloon angioplasty (73% versus 58%, P=0.03). When the results were analysed according to intention-to-treat principles, restenosis was found in 37% of the patients in the stent group and in 46% of the patients in the angioplasty group, p=0.24 (Savage et al., 1997).

These authors concluded that as compared with conventional angioplasty, stent placement in new vein-graft lesions was associated with better initial angiographic results and higher rates of procedural success. Although the luminal diameter at six months was larger in the stent group, there was no significant difference in the rate of restenosis. However, major cardiac events occurred less frequently in the stent group (Savage et al., 1997).

Percutaneous Intervention Post Coronary

(Leborgne et al., 2003).

grafts.

grafts compared to native arteries (Leborgne et al., 2003).

and reduce its fragmentation (Leborgne et al., 2003).

mortality between the two groups (Lozano et al., 2005).

protection device cannot be used (Leborgne et al., 2003).

**7. Covered stents for the treatment of saphenous vein grafts**

Artery Graft Surgery in Patients with Saphenous Vein Graft Disease – State of the Art 101

al., 2003). Direct stenting was also proposed as a strategy to reduce complications during the treatment of acute myocardial infarction, by reducing the distal embolization rate and the no-reflow phenomenon (Leborgne et al., 2003). Because saphenous vein graft lesions are more friable, the beneficial impact of direct stenting might be amplified in saphenous vein

Distal embolization and CK elevation remain a common complication after percutaneous treatment of saphenous vein grafts. The postulated mechanisms by which direct stenting minimizes distal embolisation in saphenous vein graft intervention is that by direct stenting the stent acts as scaffold to trap the friable tissue of the plaque before inflation of a balloon

In a retrospective assessment of 527 consecutive patients treated with stent implantation for saphenous vein graft stenosis, 170 patients with 229 lesions were treated with direct stenting and 357 patients with 443 lesions were treated with conventional stenting (stent deployment preceded by balloon predilation). Procedural success was high and results were similar between the 2 groups with the same rate of combined major in-hospital complications (death, Q-wave myocardial infarction, and emergent coronary artery bypass surgery). However, the maximum CK-MB elevation postprocedure (9.5 ± 18.1 versus 19.6 ± 47.8 mg/dl, P < 0.001), CK-MB elevation > 4 times the upper normal value (13.6% versus 23.0 %, P = 0.012), and non-Q wave myocardial infarction (10.7% versus 18.4%, P = 0.024) were much lower in the direct stenting group. At one year, the composite end point of death, Q wave myocardial infarction, and target lesion revascularisation was significantly lower in the direct stenting group (21.5%) versus the conventional stent group (34.3%), p = 0.021

In another retrospective study involving 117 consecutive patients who underwent stenting for at least 1 lesion located in saphenous vein grafts, 71 patients with 83 lesions had been treated with direct stenting and 46 patients with 54 lesions with stenting preceded by balloon predilatation. No differences were found between both groups regarding the success of the procedure. The distal embolisation rate was significantly higher in the predilatation group with a trend toward a greater frequency of periprocedural myocardial infarction. Median follow-up time was 36.1 months. No differences were found in long-term

Direct stenting seems to be actually the best approach for treating saphenous vein graft stenosis when it is technically feasible. This strategy may be especially useful when a distal

Despite the fact that stents have improved the outcome of percutaneous intervention of obstructed vein grafts, prognosis of patients undergoing this procedure is still poor. Targets to improve intervention in saphenous vein grafts are to inhibit distal embolisation of atherosclerotic debris and to reduce the restenosis rate, which is elevated, compared with native vessels (Stone et al., 2011). These targets provided the rationale to propose the use of a membrane-covered stent as a new option for the treatment of saphenous vein

The SAVED trial used aspirin in combination with dypiridamole and warfarin therapy post stent implantation, instead of thienopiridines.

The Venestent study was a prospective, randomised, multicenter study that compared balloon angioplasty versus elective Wiktor I stent (Medtronic, Minneapolis, MN) implantation using thienopyridines in 150 patients with de novo lesions in the body of a saphenous vein graft. Diffusely diseased grafts, ostial and restenotic lesions, total occlusions and grafts with angiographic evidence of thrombus were excluded. The primary end point of this study was the binary angiographic restenosis rate at 6-month follow-up. Restenosis was defined as diameter stenosis of more than 50%.

Seventy-three patients were randomised to balloon angioplasty and 77 patients to stent implantation. In 17 patients randomised to balloon angioplasty, a bailout stent was implanted, corresponding with a crossover rate of 23.3%.

The angiographic and the procedural success rates were comparable for the balloon and the stent group (97.3% versus 98.7% and 89.0% versus 89.6%, respectively). No difference was present between the balloon group and the stent group with respect to in-hospital major adverse cardiac events (9.6% versus 10.4%). The angiographic restenosis rate at 6-month follow-up was 32.8% in the balloon group and 19.1% in the stent group, p= 0.069. At one year follow-up, target vessel revascularisation rate was 31.4% versus 14.5%, P < 0.05; and event-free survival was 60.0% versus 76.3%, P < 0.05, for the balloon and the stent group, respectively.

The authors of this study concluded that elective stent implantation in de novo saphenous vein graft lesions was associated with a significantly lower target vessel revascularisation rate and a significant higher event-free survival at 1year follow-up as compared to balloon angioplasty (Hanekamp et al., 2003). Although the difference in restenosis rate between both groups was not statistically significant; a strong trend in favour of stenting was suggested.

As compared with balloon angioplasty elective stent implantation in selected de novo saphenous vein graft stenosis is associated with better initial angiographic results, higher rates of procedural success, lower target vessel revascularisation rate and significant higher event-free survival. It is important to note however, that the results of bare metal stents in saphenous vein grafts are less favourable than those in native vessels, with restenosis rates exceeding 30% (Savage et al., 1997; Silber et al., 2005).

#### **6. Direct stenting in saphenous vein grafts**

Lesions located in saphenous vein grafts have different characteristics to those located in native vessels with greater cellular and less fibrotic components, more necrotic debris, cholesterol, thrombi and foamy cells. Thus, one of the greatest restrictions to stent implantation with predilatation is the risk of distal embolisation, with a high incidence of peri-procedural myocardial infarction (Lozano et al., 2005).

Direct stenting is defined as stent deployment without predilation with balloon or preparation via atherectomy. Direct stenting was introduced as a strategy of percutaneous coronary revascularisation in native vessels and was equivalent or was associated with better results when compared with balloon angioplasty followed by stenting (Leborgne et

The SAVED trial used aspirin in combination with dypiridamole and warfarin therapy post

The Venestent study was a prospective, randomised, multicenter study that compared balloon angioplasty versus elective Wiktor I stent (Medtronic, Minneapolis, MN) implantation using thienopyridines in 150 patients with de novo lesions in the body of a saphenous vein graft. Diffusely diseased grafts, ostial and restenotic lesions, total occlusions and grafts with angiographic evidence of thrombus were excluded. The primary end point of this study was the binary angiographic restenosis rate at 6-month follow-up. Restenosis

Seventy-three patients were randomised to balloon angioplasty and 77 patients to stent implantation. In 17 patients randomised to balloon angioplasty, a bailout stent was

The angiographic and the procedural success rates were comparable for the balloon and the stent group (97.3% versus 98.7% and 89.0% versus 89.6%, respectively). No difference was present between the balloon group and the stent group with respect to in-hospital major adverse cardiac events (9.6% versus 10.4%). The angiographic restenosis rate at 6-month follow-up was 32.8% in the balloon group and 19.1% in the stent group, p= 0.069. At one year follow-up, target vessel revascularisation rate was 31.4% versus 14.5%, P < 0.05; and event-free survival was 60.0% versus 76.3%, P < 0.05, for the balloon and the stent group,

The authors of this study concluded that elective stent implantation in de novo saphenous vein graft lesions was associated with a significantly lower target vessel revascularisation rate and a significant higher event-free survival at 1year follow-up as compared to balloon angioplasty (Hanekamp et al., 2003). Although the difference in restenosis rate between both groups was not statistically significant; a strong trend in favour of stenting was suggested. As compared with balloon angioplasty elective stent implantation in selected de novo saphenous vein graft stenosis is associated with better initial angiographic results, higher rates of procedural success, lower target vessel revascularisation rate and significant higher event-free survival. It is important to note however, that the results of bare metal stents in saphenous vein grafts are less favourable than those in native vessels, with restenosis rates

Lesions located in saphenous vein grafts have different characteristics to those located in native vessels with greater cellular and less fibrotic components, more necrotic debris, cholesterol, thrombi and foamy cells. Thus, one of the greatest restrictions to stent implantation with predilatation is the risk of distal embolisation, with a high incidence of

Direct stenting is defined as stent deployment without predilation with balloon or preparation via atherectomy. Direct stenting was introduced as a strategy of percutaneous coronary revascularisation in native vessels and was equivalent or was associated with better results when compared with balloon angioplasty followed by stenting (Leborgne et

stent implantation, instead of thienopiridines.

was defined as diameter stenosis of more than 50%.

respectively.

implanted, corresponding with a crossover rate of 23.3%.

exceeding 30% (Savage et al., 1997; Silber et al., 2005).

**6. Direct stenting in saphenous vein grafts**

peri-procedural myocardial infarction (Lozano et al., 2005).

al., 2003). Direct stenting was also proposed as a strategy to reduce complications during the treatment of acute myocardial infarction, by reducing the distal embolization rate and the no-reflow phenomenon (Leborgne et al., 2003). Because saphenous vein graft lesions are more friable, the beneficial impact of direct stenting might be amplified in saphenous vein grafts compared to native arteries (Leborgne et al., 2003).

Distal embolization and CK elevation remain a common complication after percutaneous treatment of saphenous vein grafts. The postulated mechanisms by which direct stenting minimizes distal embolisation in saphenous vein graft intervention is that by direct stenting the stent acts as scaffold to trap the friable tissue of the plaque before inflation of a balloon and reduce its fragmentation (Leborgne et al., 2003).

In a retrospective assessment of 527 consecutive patients treated with stent implantation for saphenous vein graft stenosis, 170 patients with 229 lesions were treated with direct stenting and 357 patients with 443 lesions were treated with conventional stenting (stent deployment preceded by balloon predilation). Procedural success was high and results were similar between the 2 groups with the same rate of combined major in-hospital complications (death, Q-wave myocardial infarction, and emergent coronary artery bypass surgery). However, the maximum CK-MB elevation postprocedure (9.5 ± 18.1 versus 19.6 ± 47.8 mg/dl, P < 0.001), CK-MB elevation > 4 times the upper normal value (13.6% versus 23.0 %, P = 0.012), and non-Q wave myocardial infarction (10.7% versus 18.4%, P = 0.024) were much lower in the direct stenting group. At one year, the composite end point of death, Q wave myocardial infarction, and target lesion revascularisation was significantly lower in the direct stenting group (21.5%) versus the conventional stent group (34.3%), p = 0.021 (Leborgne et al., 2003).

In another retrospective study involving 117 consecutive patients who underwent stenting for at least 1 lesion located in saphenous vein grafts, 71 patients with 83 lesions had been treated with direct stenting and 46 patients with 54 lesions with stenting preceded by balloon predilatation. No differences were found between both groups regarding the success of the procedure. The distal embolisation rate was significantly higher in the predilatation group with a trend toward a greater frequency of periprocedural myocardial infarction. Median follow-up time was 36.1 months. No differences were found in long-term mortality between the two groups (Lozano et al., 2005).

Direct stenting seems to be actually the best approach for treating saphenous vein graft stenosis when it is technically feasible. This strategy may be especially useful when a distal protection device cannot be used (Leborgne et al., 2003).

### **7. Covered stents for the treatment of saphenous vein grafts**

Despite the fact that stents have improved the outcome of percutaneous intervention of obstructed vein grafts, prognosis of patients undergoing this procedure is still poor. Targets to improve intervention in saphenous vein grafts are to inhibit distal embolisation of atherosclerotic debris and to reduce the restenosis rate, which is elevated, compared with native vessels (Stone et al., 2011). These targets provided the rationale to propose the use of a membrane-covered stent as a new option for the treatment of saphenous vein grafts.

Percutaneous Intervention Post Coronary

the expectations.

al., 2003).

were limited by short-term follow-up.

followed for a total duration of 5 years.

interval: 0.72 to 1.75, p = 0.63).

randomised to the JOSTENT versus any bare-metal stent.

Artery Graft Surgery in Patients with Saphenous Vein Graft Disease – State of the Art 103

Postprocedural minimal luminal diameter was comparable between the two groups.

At follow-up, there were no statistically significant differences in minimal luminal diameter or percent stenosis between the groups. With respect to the primary end point restenosis rate at six months, there was also no significant difference between the Flex (20%) and the Stentgraft groups (29%), p=0.15. The restenosis rate in both groups was lower in this study than in other contemporary studies involving vein graft stenting, probably related to patient selection. There was a nonsignificant trend toward a higher late occlusion rate in the Stentgraft group (7% versus 16%, p= 0.069) at follow-up. After a mean observation period of 14 months, cumulative event rates (death, myocardial infarction, or target lesion revascularisation were comparable in the two groups (31% versus 31%, p = 0.93) (Schächinger et al., 2003). The outcome of the stent graft group in this study was worse than

The RECOVERS (Randomized Evaluation of polytetrafluoroethylene COVERed stent in Saphenous vein grafts) trial was a prospective, multicenter trial that randomized 301 patients with saphenous vein graft lesions to either the polytetrafluoroethylene-covered JOSTENT stent-graft or the JoFlex stent. Angiographic and procedural success rates were similar between the 2 groups (97.4% versus 97.9% and 87.3% versus 93.8%, respectively). The incidence of 30-day of major adverse cardiac events was higher in the JOSTENT stentgraft group (10.9% versus 4.1%, p = 0.047) and was mainly attributed to myocardial infarction (10.3% versus 3.4%, p = 0.037). The primary end point, the restenosis rate at 6 month follow-up, was similar between the two groups (24.2% versus 24.8%, p =0.237). Although the 6-month non Q-wave myocardial infarction rate was higher in the stent-graft group (12.8% versus 4.1%, p =0.013), the cumulative major adverse cardiac event rate was not different (23.1% versus 15.9%, p=0.153). This study also failed to demonstrate a beneficial effect of the JOSTENT stent-graft for saphenous vein graft treatment (Stankovic et

The prior Trials of the JOSTENT stent-graft did not mandate high-pressure implantation or prolonged dual antiplatelet therapy, measures that might be necessary to mechanically optimize the implant and facilitate endothelialisation without thrombosis. Moreover, they

The BARRICADE (Barrier Approach to restenosis: Restrict Intima to Curtail Adverse Events) trial was a prospective, multicenter study that included 243 patients that were

JOSTENT post-dilation to ≥ 18 atmospheres was mandated to overcome limitations of prior studies, as was the use of dual antiplatelet therapy for ≥ 8 months, and all patients were

The primary end point of in-lesion binary restenosis at 8 months was not statistically different between the groups and occurred in 31.8% of lesions treated with the JOSTENT versus 28.4% of lesions treated with bare-metal stents (relative risk: 1.12, 95% confidence

At 9 months, the major secondary end point of target vessel failure (death, myocardial infarction, or clinically driven target vessel revascularisation) occurred in 32.2% of patients

Periprocedural events during the intervention were similar between groups.

Initial experiences using the JOSTENT coronary stent graft (Jomed GmbH, Rangendingen, Germany) were promising when used in saphenous vein grafts (Elsner et al., 1999).

The JOSTENT stent-graft consists of a distensible polytetrafluoroethylene (PTFE) membrane sandwiched between two 316L stainless steel slotted tube, balloon-expandable stents. This device is currently available as the GraftMaster (Abbott Vascular, Santa Clara, California) for treatment of life-threatening coronary perforations (Figure 1).

Hypothetical benefits of elective use of the JOSTENT PTFE stent-graft in saphenous vein grafts included reduced periprocedural myocardial infarction (by trapping potentially embolic degenerated atherosclerotic debris behind the PTFE membrane) and decreased restenosis (by serving as a barrier isolating the lumen from smooth muscle cell proliferation, migration, and extracellular matrix production arising from the media) (Stone et al., 2011).

Results of a German multicenter registry suggested that the PTFE-membrane-covered stent appeared to be a safe and efficient treatment strategy for obstructed vein grafts with restenosis rates of about 17% (Baldus et al., 2000). Several prospective, randomised, multicenter trials were then conducted to compare the JOSTENT stent-graft with different conventional stents in patients undergoing percutaneous coronary intervention of obstructed saphenous vein grafts.

Fig. 1. Image of the GraftMaster polytetrafluoroethylene membrane covered stent. Courtesy of Abbott Vascular.

The STING (STents IN Grafts) trial was a prospective, multicenter study that included a total of 211 patients who were randomly assigned to receive either a Jostent Flex coronary stent or a JOSTENT stent-graft for the treatment of de novo lesions in saphenous vein grafts with a lesion length between 5 and 45 mm and a reference diameter between 3.0 and 5.0 mm. Patients were pretreated with aspirin (100 mg per day). Ticlopidine (500 mg per day) or clopidogrel (75 mg per day) were started after loading doses at the day of the procedure and continued for three months.

The primary end point was binary restenosis rate at six months by core lab quantitative coronary angiography.

Initial experiences using the JOSTENT coronary stent graft (Jomed GmbH, Rangendingen,

The JOSTENT stent-graft consists of a distensible polytetrafluoroethylene (PTFE) membrane sandwiched between two 316L stainless steel slotted tube, balloon-expandable stents. This device is currently available as the GraftMaster (Abbott Vascular, Santa Clara, California)

Hypothetical benefits of elective use of the JOSTENT PTFE stent-graft in saphenous vein grafts included reduced periprocedural myocardial infarction (by trapping potentially embolic degenerated atherosclerotic debris behind the PTFE membrane) and decreased restenosis (by serving as a barrier isolating the lumen from smooth muscle cell proliferation, migration, and extracellular matrix production arising from the media) (Stone et al., 2011). Results of a German multicenter registry suggested that the PTFE-membrane-covered stent appeared to be a safe and efficient treatment strategy for obstructed vein grafts with restenosis rates of about 17% (Baldus et al., 2000). Several prospective, randomised, multicenter trials were then conducted to compare the JOSTENT stent-graft with different conventional stents in patients undergoing percutaneous coronary intervention of

Fig. 1. Image of the GraftMaster polytetrafluoroethylene membrane covered stent. Courtesy

The STING (STents IN Grafts) trial was a prospective, multicenter study that included a total of 211 patients who were randomly assigned to receive either a Jostent Flex coronary stent or a JOSTENT stent-graft for the treatment of de novo lesions in saphenous vein grafts with a lesion length between 5 and 45 mm and a reference diameter between 3.0 and 5.0 mm. Patients were pretreated with aspirin (100 mg per day). Ticlopidine (500 mg per day) or clopidogrel (75 mg per day) were started after loading doses at the day of the procedure and

The primary end point was binary restenosis rate at six months by core lab quantitative

Germany) were promising when used in saphenous vein grafts (Elsner et al., 1999).

for treatment of life-threatening coronary perforations (Figure 1).

obstructed saphenous vein grafts.

of Abbott Vascular.

continued for three months.

coronary angiography.

Postprocedural minimal luminal diameter was comparable between the two groups. Periprocedural events during the intervention were similar between groups.

At follow-up, there were no statistically significant differences in minimal luminal diameter or percent stenosis between the groups. With respect to the primary end point restenosis rate at six months, there was also no significant difference between the Flex (20%) and the Stentgraft groups (29%), p=0.15. The restenosis rate in both groups was lower in this study than in other contemporary studies involving vein graft stenting, probably related to patient selection. There was a nonsignificant trend toward a higher late occlusion rate in the Stentgraft group (7% versus 16%, p= 0.069) at follow-up. After a mean observation period of 14 months, cumulative event rates (death, myocardial infarction, or target lesion revascularisation were comparable in the two groups (31% versus 31%, p = 0.93) (Schächinger et al., 2003). The outcome of the stent graft group in this study was worse than the expectations.

The RECOVERS (Randomized Evaluation of polytetrafluoroethylene COVERed stent in Saphenous vein grafts) trial was a prospective, multicenter trial that randomized 301 patients with saphenous vein graft lesions to either the polytetrafluoroethylene-covered JOSTENT stent-graft or the JoFlex stent. Angiographic and procedural success rates were similar between the 2 groups (97.4% versus 97.9% and 87.3% versus 93.8%, respectively). The incidence of 30-day of major adverse cardiac events was higher in the JOSTENT stentgraft group (10.9% versus 4.1%, p = 0.047) and was mainly attributed to myocardial infarction (10.3% versus 3.4%, p = 0.037). The primary end point, the restenosis rate at 6 month follow-up, was similar between the two groups (24.2% versus 24.8%, p =0.237). Although the 6-month non Q-wave myocardial infarction rate was higher in the stent-graft group (12.8% versus 4.1%, p =0.013), the cumulative major adverse cardiac event rate was not different (23.1% versus 15.9%, p=0.153). This study also failed to demonstrate a beneficial effect of the JOSTENT stent-graft for saphenous vein graft treatment (Stankovic et al., 2003).

The prior Trials of the JOSTENT stent-graft did not mandate high-pressure implantation or prolonged dual antiplatelet therapy, measures that might be necessary to mechanically optimize the implant and facilitate endothelialisation without thrombosis. Moreover, they were limited by short-term follow-up.

The BARRICADE (Barrier Approach to restenosis: Restrict Intima to Curtail Adverse Events) trial was a prospective, multicenter study that included 243 patients that were randomised to the JOSTENT versus any bare-metal stent.

JOSTENT post-dilation to ≥ 18 atmospheres was mandated to overcome limitations of prior studies, as was the use of dual antiplatelet therapy for ≥ 8 months, and all patients were followed for a total duration of 5 years.

The primary end point of in-lesion binary restenosis at 8 months was not statistically different between the groups and occurred in 31.8% of lesions treated with the JOSTENT versus 28.4% of lesions treated with bare-metal stents (relative risk: 1.12, 95% confidence interval: 0.72 to 1.75, p = 0.63).

At 9 months, the major secondary end point of target vessel failure (death, myocardial infarction, or clinically driven target vessel revascularisation) occurred in 32.2% of patients

Percutaneous Intervention Post Coronary

indications (Michishita, 2011).

al., 2007).

(p=0.43).

Artery Graft Surgery in Patients with Saphenous Vein Graft Disease – State of the Art 105

event rates were comparable between groups. At 8 months, percent diameter stenosis was comparable between groups (30.9% Symbiot, 31.9% bare metal stent, p=0.80). Although the rates of binary restenosis in the stented segment were similar (29.1% Symbiot, 21.9% bare metal stent, p=0.17), more patients in the Symbiot group had binary restenosis at the proximal edge (9.0% Symbiot, 1.8% bare metal stent, p=0.0211). Overall major adverse cardiac event rates at 8 months were comparable for both groups, with 30.6% of Symbiot patients and 26.6% of bare metal stents patients experiencing major adverse cardiac events

This study failed to show an advantage for the Symbiot stent in the treatment of degenerated saphenous vein grafts. These authors concluded that the polytetrafluoroethylene covering does not appear to act as a barrier to reduce neointimal hyperplasia (Turco et al., 2006).

The hypothesis that covered stents for the treatment of saphenous vein grafts may reduce periprocedural myocardial infarction and decrease restenosis seems to have been invalidated. Covered stents should be reserved for life-threatening perforations of the

In recent times, drug-eluting stents have become the leading device for the treatment of native coronary artery disease, because of the reduction in the incidence of restenosis, target lesion revascularisation, and target vessel revascularisation compared with bare metal stents (Michishita, 2011). Drug-eluting stents were developed to remove the incidence of restenosis and target lesion revascularisation only, but it has been hypothesised that drug eluting stents can improve the mortality and myocardial infarction rates, compared with bare metal stents, because their effect on reducing restenosis is remarkable and because restenosis after bare metal stent implantation could manifest as acute coronary syndrome in some patients. In real-world nonrandomised observational studies with large numbers of patients, but with a potential for selection bias and residual confounding, use of drug-eluting stents in native coronary arteries has been associated with reduced mortality and myocardial infarction rates (Michishita, 2011). In randomized controlled trials, no significant differences have been observed in the long-term mortality or myocardial infarction rate after the use of drugeluting stents or bare metal stents in native coronary arteries for either off-label or on-label

Although drug-eluting stents have been a major advance in interventional cardiology, evidence for using these devices does not exist for all types of lesions or for all subsets of patients. One area where data have been lacking is the indication of diseased aortocoronary saphenous vein grafts (Bittl, 2009). Lesions in saphenous vein grafts have been poorly represented if not totally excluded in pivotal drug-eluting stent trials. However, this lesion subset represents a consistent proportion of lesions in which percutaneous procedures are performed, up to 10% to 15%in most centres (Baim, 2003 & Vermeersch et

The current limited evidence of drug eluting stent use in saphenous vein graft intervention comes mainly from a few small but well performed mechanistic randomised trials, multiple larger observational studies and more recently from several meta-analysis that have

included evidence from these randomised trials and observational studies.

**8. Drug eluting stents in the treatment of saphenous vein graft disease**

coronary vasculature (Lansky et al., 2006; Stone et al., 2011).

treated with the JOSTENT versus 22.1% of patients treated with bare metal stents (hazard ratio: 1.54, 95% CI: 0.94 to 2.53, p = 0.08). During long-term follow-up, significantly more events accrued in the JOSTENT arm such that by 5 years target vessel failure had occurred in 68.3% of JOSTENT patients versus 51.8% of bare metal stent patients (hazard ratio: 1.59, 95% CI: 1.13 to 2.23, p =0.007). Although there were no statistically significant differences between the 2 stent types in the rates of myocardial infarction or stent thrombosis, target vessel occlusion was noted more frequently in the JOSTENT arm during long-term followup. This study was designed to overcome several potentially important limitations from prior randomised trials of the JOSTENT stent-graft in diseased saphenous vein grafts, despite this stent-grafts had a grater failure rate when used for this application than bare metal stents (Stone et al., 2011).

Covered stents showed a tendency toward a higher rate of total occlusions at follow-up. It has been speculated that a postponed re-endothelialisation or enhanced thrombogenicity of the PTFE membrane might predispose for late thrombotic occlusions. However, the clinical course of most documented late occlusions was surprisingly benign, with only a few cases associated with a myocardial infarction. The fact that late occlusions >150 days were not associated with myocardial infarction might indicate that progressively proliferating restenosis, rather than acute thrombosis, might be the mechanism of late occlusion in these patients (Schächinger et al., 2003)

The Symbiot self expanding polytetrafluoroethylene covered stent (Boston Scientific Corporation, Natick, MA) was developed to reduce the potential for acute and long term complications associated with percutaneous intervention in degenerated saphenous vein conduits. The SymbiotTM covered stent system consists of a self-expanding, nitinol, multisegmented stent encased within a thin (13µm), porous, polytetrafluoroethylene polymer membrane designed to maintain cellular viability of the adjacent tissue.

Two nonrandomized registries were conducted with the Symbiot stent. Symbiot I enrolled 25 patients. Of the 16 patients with angiographic follow-up at 6 months, the mean percent diameter stenosis was 18.8 ± 28.6%, and 19% had in-stent binary restenosis (unpublished data, Boston Scientific corporation).

Symbiot II, which enrolled 77 patients (58 with angiographic follow-up), demonstrated excellent outcome for the Symbiot stent with a mean percent diameter stenosis of 26.1 ± 20.9%, an in-stent binary restenosis rate of 7.0%, and an overall major adverse cardiac event rate of 14.3% at 6 months. These two studies demonstrated promising results but were limited by the absence of an active control group for comparison and small sample size.

The Symbiot III trial was designed to evaluate the clinical and angiographic outcomes of the Symbiot covered stent versus bare metal stents for the treatment of saphenous vein graft disease. The Symbiot III trial was a prospective randomized trial of 400 patients, with 201 patients in the Symbiot covered stent group and 199 in the bare metal stent group. Randomization was stratified based on the intended use of embolic protection devices and glycoprotein IIb/IIIa inhibitors. The primary endpoint of the study was percent diameter stenosis at 8 months, as measured by quantitative coronary angiography. Secondary endpoints included major adverse cardiac events, consisting of cardiac death, myocardial infarction, and target vessel revascularization. In-hospital and 30-day overall major adverse

treated with the JOSTENT versus 22.1% of patients treated with bare metal stents (hazard ratio: 1.54, 95% CI: 0.94 to 2.53, p = 0.08). During long-term follow-up, significantly more events accrued in the JOSTENT arm such that by 5 years target vessel failure had occurred in 68.3% of JOSTENT patients versus 51.8% of bare metal stent patients (hazard ratio: 1.59, 95% CI: 1.13 to 2.23, p =0.007). Although there were no statistically significant differences between the 2 stent types in the rates of myocardial infarction or stent thrombosis, target vessel occlusion was noted more frequently in the JOSTENT arm during long-term followup. This study was designed to overcome several potentially important limitations from prior randomised trials of the JOSTENT stent-graft in diseased saphenous vein grafts, despite this stent-grafts had a grater failure rate when used for this application than bare

Covered stents showed a tendency toward a higher rate of total occlusions at follow-up. It has been speculated that a postponed re-endothelialisation or enhanced thrombogenicity of the PTFE membrane might predispose for late thrombotic occlusions. However, the clinical course of most documented late occlusions was surprisingly benign, with only a few cases associated with a myocardial infarction. The fact that late occlusions >150 days were not associated with myocardial infarction might indicate that progressively proliferating restenosis, rather than acute thrombosis, might be the mechanism of late occlusion in these

The Symbiot self expanding polytetrafluoroethylene covered stent (Boston Scientific Corporation, Natick, MA) was developed to reduce the potential for acute and long term complications associated with percutaneous intervention in degenerated saphenous vein conduits. The SymbiotTM covered stent system consists of a self-expanding, nitinol, multisegmented stent encased within a thin (13µm), porous, polytetrafluoroethylene polymer

Two nonrandomized registries were conducted with the Symbiot stent. Symbiot I enrolled 25 patients. Of the 16 patients with angiographic follow-up at 6 months, the mean percent diameter stenosis was 18.8 ± 28.6%, and 19% had in-stent binary restenosis (unpublished

Symbiot II, which enrolled 77 patients (58 with angiographic follow-up), demonstrated excellent outcome for the Symbiot stent with a mean percent diameter stenosis of 26.1 ± 20.9%, an in-stent binary restenosis rate of 7.0%, and an overall major adverse cardiac event rate of 14.3% at 6 months. These two studies demonstrated promising results but were limited by the absence of an active control group for comparison and small sample

The Symbiot III trial was designed to evaluate the clinical and angiographic outcomes of the Symbiot covered stent versus bare metal stents for the treatment of saphenous vein graft disease. The Symbiot III trial was a prospective randomized trial of 400 patients, with 201 patients in the Symbiot covered stent group and 199 in the bare metal stent group. Randomization was stratified based on the intended use of embolic protection devices and glycoprotein IIb/IIIa inhibitors. The primary endpoint of the study was percent diameter stenosis at 8 months, as measured by quantitative coronary angiography. Secondary endpoints included major adverse cardiac events, consisting of cardiac death, myocardial infarction, and target vessel revascularization. In-hospital and 30-day overall major adverse

membrane designed to maintain cellular viability of the adjacent tissue.

metal stents (Stone et al., 2011).

patients (Schächinger et al., 2003)

data, Boston Scientific corporation).

size.

event rates were comparable between groups. At 8 months, percent diameter stenosis was comparable between groups (30.9% Symbiot, 31.9% bare metal stent, p=0.80). Although the rates of binary restenosis in the stented segment were similar (29.1% Symbiot, 21.9% bare metal stent, p=0.17), more patients in the Symbiot group had binary restenosis at the proximal edge (9.0% Symbiot, 1.8% bare metal stent, p=0.0211). Overall major adverse cardiac event rates at 8 months were comparable for both groups, with 30.6% of Symbiot patients and 26.6% of bare metal stents patients experiencing major adverse cardiac events (p=0.43).

This study failed to show an advantage for the Symbiot stent in the treatment of degenerated saphenous vein grafts. These authors concluded that the polytetrafluoroethylene covering does not appear to act as a barrier to reduce neointimal hyperplasia (Turco et al., 2006).

The hypothesis that covered stents for the treatment of saphenous vein grafts may reduce periprocedural myocardial infarction and decrease restenosis seems to have been invalidated. Covered stents should be reserved for life-threatening perforations of the coronary vasculature (Lansky et al., 2006; Stone et al., 2011).

## **8. Drug eluting stents in the treatment of saphenous vein graft disease**

In recent times, drug-eluting stents have become the leading device for the treatment of native coronary artery disease, because of the reduction in the incidence of restenosis, target lesion revascularisation, and target vessel revascularisation compared with bare metal stents (Michishita, 2011). Drug-eluting stents were developed to remove the incidence of restenosis and target lesion revascularisation only, but it has been hypothesised that drug eluting stents can improve the mortality and myocardial infarction rates, compared with bare metal stents, because their effect on reducing restenosis is remarkable and because restenosis after bare metal stent implantation could manifest as acute coronary syndrome in some patients. In real-world nonrandomised observational studies with large numbers of patients, but with a potential for selection bias and residual confounding, use of drug-eluting stents in native coronary arteries has been associated with reduced mortality and myocardial infarction rates (Michishita, 2011). In randomized controlled trials, no significant differences have been observed in the long-term mortality or myocardial infarction rate after the use of drugeluting stents or bare metal stents in native coronary arteries for either off-label or on-label indications (Michishita, 2011).

Although drug-eluting stents have been a major advance in interventional cardiology, evidence for using these devices does not exist for all types of lesions or for all subsets of patients. One area where data have been lacking is the indication of diseased aortocoronary saphenous vein grafts (Bittl, 2009). Lesions in saphenous vein grafts have been poorly represented if not totally excluded in pivotal drug-eluting stent trials. However, this lesion subset represents a consistent proportion of lesions in which percutaneous procedures are performed, up to 10% to 15%in most centres (Baim, 2003 & Vermeersch et al., 2007).

The current limited evidence of drug eluting stent use in saphenous vein graft intervention comes mainly from a few small but well performed mechanistic randomised trials, multiple larger observational studies and more recently from several meta-analysis that have included evidence from these randomised trials and observational studies.

Percutaneous Intervention Post Coronary

Artery Graft Surgery in Patients with Saphenous Vein Graft Disease – State of the Art 107

Death occurred in 11 patients (7 cardiac, of which one was caused by a very late stent thrombosis and 3 were sudden) after Sirolimus-eluting stent (29% [95% confidence limits 17% to 45%]) versus 0 after bare metal stents (0% [0% to 9%]) with an absolute difference of 29% (95% confidence interval 14% to 45%, p < 0.001). The overall rate of definite angiographically documented stent thrombosis was 5% in the Sirolimus-eluting stent group (2 of 38, both very late) versus 0% in the bare metal stent group (p=0.49), whereas the rate of any possible stent thrombosis was 13% (5 of 38, 2 late and 3 very late) after Sirolimus-eluting stents versus 0% after bare metal stents (Fischer exact test 2-sided p value = 0.054; log rank test = 0.022). The rates of myocardial infarction and target vessel revascularisation were not different; 18% and 34% after Sirolimus-eluting stents, respectively, versus 5% and 38% after

In this extended post hoc analysis of the RRISC trial, patients treated with Sirolimus-eluting stents showed a significant increase in total mortality and the benefits of Sirolimus-eluting stents in terms of reduced revascularisation procedures shown at 6 months (Vermeersch et al., 2006) was no longer evident up to 3 years, suggesting that in saphenous vein grafts there can be a potential late catch-up phenomenon leading to a lack of benefit of Sirolimus-eluting stents over bare metal stents in reduction of clinical restenosis (Vermeersch et al., 2007).

This study had several major limitations. First, the sample size of patients was small, thus the results could be underpowered to appropriately address specific questions and can be prone to type I and type II statistical error. Second, the recommended duration of double antiplatelet therapy was only mandatory for at least 2 months in this study. Recent evidence has shown that double antiplatelet therapy should be recommended in all patients receiving drug-eluting stents for at least 12 months (Grines et al., 2007). Therefore, it cannot be excluded that some of the events described in the DELAYED RRISC study could be explained by "premature" discontinuation of dual antiplatelet therapy. Third, this study presented a secondary post-hoc analysis; thus, the main end point (death) was not prespecified at the moment of the beginning of the trial (which was powered for a 6-month difference in angiographic late loss analysis). The authors of this study concluded that given that the observations seen in this secondary post hoc analysis may have arisen from the play of chance or other clinical factors unrelated to stent type, further studies were required before conclusions could be made about the safety or harm of using Sirolimus-eluting stents

The SOS (Stenting Of Saphenous Vein Grafts) Trial was a randomised, controlled multicenter, prospective trial. Patients with one or more de novo or restenotic lesions in a saphenous vein graft that were between 2.5 and 4.0 mm in diameter were randomised to a polymer-based paclitaxel-eluting stent (Taxus, Boston Scientific, Natick, Massachusetts) or a

Eighty patients with 112 lesions in 88 saphenous vein grafts were randomised to receive a paclitaxel-eluting stent (41 patients, 45 grafts, 57 lesions) or to receive a bare metal stent (39

The primary end point of the study was binary angiographic restenosis/lesion, defined as a stenosis of ≥ 50% of the minimal luminal diameter in the target saphenous vein graft segment at 12-month angiographic follow-up. The use of embolic protection devices and intravascular ultrasound were strongly encouraged. Aspirin was administered indefinitely

bare metal stents, respectively (p = 0.15 and p = 0.74, respectively).

for saphenous vein graft lesions (Vermeersch et al., 2007).

patients, 43 grafts, 55 lesions).

bare metal stent with similar design (Express2, Boston Scientific).

#### **8.1 Randomized trials**

The RRISC (Reduction of Restenosis In Saphenous vein grafts with Cypher sirolimus-eluting stent) trial was a randomised, double blind, non-industry sponsored trial performed in a single centre. Patients with one or more "de novo" target lesions localized in ore or more diseased saphenous vein grafts with a reference vessel diameter > 2.5 and < 4.0 mm were allocated randomly to treatment with Cypher Sirolimus-eluting stent or BX-Velocity bare metal stent (both from Cordis, Johnson & Johnson, Warren, New Jersey). Direct stenting was promoted. Clopidogrel was administered for 2 months in all patients. All were scheduled to undergo six-month coronary angiography.

A total of 75 patients with 96 lesions localized in 80 diseased saphenous vein grafts were included: 38 patients received 60 Sirolimus-eluting stents for 47 lesions, whereas 37 patients received 54 bare metal stents for 49 lesions. Distal protection devices were used in more than 80% of the lesions treated.

The six-month in-stent late lumen loss (primary end point of the study) was significantly reduced in Sirolimus-eluting stents (0.38 ± 0.51 mm versus 0.79 ± 0.66 mm in bare metal stents, p = 0.001). Binary in-stent and in-segment restenosis were reduced in the Sirolimuseluting stents, 11.3% versus 30.6% (relative risk 0.37; 95% confidence interval 0.15 to 0.97, p = 0.024) and 13.6% versus 32.6% (relative risk 0.42: 95% confidence interval 0.18 to 0.97, p = 0.031), respectively. The pattern of restenosis was different between both groups. After Sirolimus-eluting stent implantation, most restenosis were focal (83.3%) whereas after bare metal stent implantation most restenosis (62.5%) had a non-focal pattern.

Target lesion and vessel revascularisation rates (all ischaemia-driven percutaneous interventions) were significantly reduced in the Sirolimus-eluting stent group, 5.3% versus 21.6% (relative risk 0.24; 95% confidence interval 0.05 to 1.0, p = 0.047) and 5.3% versus 27% (relative risk 0.19; 95% confidence interval 0.05 to 0.83, p = 0.012) respectively. Death and myocardial infarction rates were not different between groups.

The RRISC Trial suggested a benefit for Sirolimus-eluting stents over bare metal stents in diseased saphenous vein grafts mainly for a reduced revascularisation procedure rate at a follow-up of 6 months. The small sample size of this study made it underpowered for major clinical outcomes (Vermeersch et al., 2006).

Great focus has recently been put on the evaluation of long-term follow-up of drug-eluting stents in native coronary arteries, mainly after publication of original and meta-analytical studies showing a possible increase in "hard" adverse events, specifically very late stent thrombosis, after drug-eluting stent deployment with respect to bare metal stents (Vermeersch et al., 2007).

Due to the lack in long-term data in patients with saphenous vein graft lesions and to offer additional information to the debate on safety of Sirolimus-eluting stents, the investigators of the RRISC trial performed a clinical follow-up evaluation of the 75 patients enrolled in the RRISC trial up to 3 years, focusing specifically on all-cause mortality and was published as the DELAYED RRISC (Death and Events at Long-term follow-up AnalYsis: Extended Duration of the Reduction of Restenosis In Saphenous vein grafts with Cypher stent) trial. The new post-hoc main end point of this secondary long-term follow-up analysis was allcause mortality.

The RRISC (Reduction of Restenosis In Saphenous vein grafts with Cypher sirolimus-eluting stent) trial was a randomised, double blind, non-industry sponsored trial performed in a single centre. Patients with one or more "de novo" target lesions localized in ore or more diseased saphenous vein grafts with a reference vessel diameter > 2.5 and < 4.0 mm were allocated randomly to treatment with Cypher Sirolimus-eluting stent or BX-Velocity bare metal stent (both from Cordis, Johnson & Johnson, Warren, New Jersey). Direct stenting was promoted. Clopidogrel was administered for 2 months in all patients. All were scheduled to

A total of 75 patients with 96 lesions localized in 80 diseased saphenous vein grafts were included: 38 patients received 60 Sirolimus-eluting stents for 47 lesions, whereas 37 patients received 54 bare metal stents for 49 lesions. Distal protection devices were used in more than

The six-month in-stent late lumen loss (primary end point of the study) was significantly reduced in Sirolimus-eluting stents (0.38 ± 0.51 mm versus 0.79 ± 0.66 mm in bare metal stents, p = 0.001). Binary in-stent and in-segment restenosis were reduced in the Sirolimuseluting stents, 11.3% versus 30.6% (relative risk 0.37; 95% confidence interval 0.15 to 0.97, p = 0.024) and 13.6% versus 32.6% (relative risk 0.42: 95% confidence interval 0.18 to 0.97, p = 0.031), respectively. The pattern of restenosis was different between both groups. After Sirolimus-eluting stent implantation, most restenosis were focal (83.3%) whereas after bare

Target lesion and vessel revascularisation rates (all ischaemia-driven percutaneous interventions) were significantly reduced in the Sirolimus-eluting stent group, 5.3% versus 21.6% (relative risk 0.24; 95% confidence interval 0.05 to 1.0, p = 0.047) and 5.3% versus 27% (relative risk 0.19; 95% confidence interval 0.05 to 0.83, p = 0.012) respectively. Death and

The RRISC Trial suggested a benefit for Sirolimus-eluting stents over bare metal stents in diseased saphenous vein grafts mainly for a reduced revascularisation procedure rate at a follow-up of 6 months. The small sample size of this study made it underpowered for major

Great focus has recently been put on the evaluation of long-term follow-up of drug-eluting stents in native coronary arteries, mainly after publication of original and meta-analytical studies showing a possible increase in "hard" adverse events, specifically very late stent thrombosis, after drug-eluting stent deployment with respect to bare metal stents

Due to the lack in long-term data in patients with saphenous vein graft lesions and to offer additional information to the debate on safety of Sirolimus-eluting stents, the investigators of the RRISC trial performed a clinical follow-up evaluation of the 75 patients enrolled in the RRISC trial up to 3 years, focusing specifically on all-cause mortality and was published as the DELAYED RRISC (Death and Events at Long-term follow-up AnalYsis: Extended Duration of the Reduction of Restenosis In Saphenous vein grafts with Cypher stent) trial. The new post-hoc main end point of this secondary long-term follow-up analysis was all-

metal stent implantation most restenosis (62.5%) had a non-focal pattern.

myocardial infarction rates were not different between groups.

clinical outcomes (Vermeersch et al., 2006).

(Vermeersch et al., 2007).

cause mortality.

**8.1 Randomized trials**

80% of the lesions treated.

undergo six-month coronary angiography.

Death occurred in 11 patients (7 cardiac, of which one was caused by a very late stent thrombosis and 3 were sudden) after Sirolimus-eluting stent (29% [95% confidence limits 17% to 45%]) versus 0 after bare metal stents (0% [0% to 9%]) with an absolute difference of 29% (95% confidence interval 14% to 45%, p < 0.001). The overall rate of definite angiographically documented stent thrombosis was 5% in the Sirolimus-eluting stent group (2 of 38, both very late) versus 0% in the bare metal stent group (p=0.49), whereas the rate of any possible stent thrombosis was 13% (5 of 38, 2 late and 3 very late) after Sirolimus-eluting stents versus 0% after bare metal stents (Fischer exact test 2-sided p value = 0.054; log rank test = 0.022). The rates of myocardial infarction and target vessel revascularisation were not different; 18% and 34% after Sirolimus-eluting stents, respectively, versus 5% and 38% after bare metal stents, respectively (p = 0.15 and p = 0.74, respectively).

In this extended post hoc analysis of the RRISC trial, patients treated with Sirolimus-eluting stents showed a significant increase in total mortality and the benefits of Sirolimus-eluting stents in terms of reduced revascularisation procedures shown at 6 months (Vermeersch et al., 2006) was no longer evident up to 3 years, suggesting that in saphenous vein grafts there can be a potential late catch-up phenomenon leading to a lack of benefit of Sirolimus-eluting stents over bare metal stents in reduction of clinical restenosis (Vermeersch et al., 2007).

This study had several major limitations. First, the sample size of patients was small, thus the results could be underpowered to appropriately address specific questions and can be prone to type I and type II statistical error. Second, the recommended duration of double antiplatelet therapy was only mandatory for at least 2 months in this study. Recent evidence has shown that double antiplatelet therapy should be recommended in all patients receiving drug-eluting stents for at least 12 months (Grines et al., 2007). Therefore, it cannot be excluded that some of the events described in the DELAYED RRISC study could be explained by "premature" discontinuation of dual antiplatelet therapy. Third, this study presented a secondary post-hoc analysis; thus, the main end point (death) was not prespecified at the moment of the beginning of the trial (which was powered for a 6-month difference in angiographic late loss analysis). The authors of this study concluded that given that the observations seen in this secondary post hoc analysis may have arisen from the play of chance or other clinical factors unrelated to stent type, further studies were required before conclusions could be made about the safety or harm of using Sirolimus-eluting stents for saphenous vein graft lesions (Vermeersch et al., 2007).

The SOS (Stenting Of Saphenous Vein Grafts) Trial was a randomised, controlled multicenter, prospective trial. Patients with one or more de novo or restenotic lesions in a saphenous vein graft that were between 2.5 and 4.0 mm in diameter were randomised to a polymer-based paclitaxel-eluting stent (Taxus, Boston Scientific, Natick, Massachusetts) or a bare metal stent with similar design (Express2, Boston Scientific).

Eighty patients with 112 lesions in 88 saphenous vein grafts were randomised to receive a paclitaxel-eluting stent (41 patients, 45 grafts, 57 lesions) or to receive a bare metal stent (39 patients, 43 grafts, 55 lesions).

The primary end point of the study was binary angiographic restenosis/lesion, defined as a stenosis of ≥ 50% of the minimal luminal diameter in the target saphenous vein graft segment at 12-month angiographic follow-up. The use of embolic protection devices and intravascular ultrasound were strongly encouraged. Aspirin was administered indefinitely

Percutaneous Intervention Post Coronary

studies.

**8.2 Meta-analysis**

graft age (p = 0.005).

Artery Graft Surgery in Patients with Saphenous Vein Graft Disease – State of the Art 109

The results of randomised trials of drug-eluting stents in saphenous vein grafts can not be extrapolated to large saphenous vein grafts (with a reference vessel diameter > 4.0 mm) or to totally occluded vein grafts because they were excluded from randomisation in those

Several meta-analysis including evidence from randomised trials and observational studies that compared the use of drug-eluting stents versus bare metal stents in the percutaneous

A meta-analysis by Lupi et al included 23 studies comparing drug-eluting stents versus bare metal stents enrolling a total of 7,090 patients with saphenous vein graft disease. Three of the 23 studies included in this meta-analysis were randomised controlled trials and the remaining 20 were non-randomised studies. These authors included in their meta-analysis randomised and/or non-randomised studies, studies reporting clinical outcomes as overall death and/or acute myocardial infarction and/or target vessel revascularisation and studies

Patients treated by drug-eluting stents showed lower overall mortality rates with marginal statistical significance compared with those treated by bare metal stents (odds ratio, 0.63; confidence interval, 0.40-0.99; p =0.05; 7.0% versus 15.3% respectively). Subgroup analysis revealed a difference in the outcome between randomised and non-randomised studies. In particular, a survival benefit following drug eluting stent implantation was observed in nonrandomised studies (odds ratio, 0.57; confidence interval, 0.36-0.90; p=0.02), but not in randomised controlled trials (odds ratio, 2.23; confidence interval, 0.15-32.35; p=0.56).

Patients treated by drug-eluting stents showed no benefit in myocardial infarction rates compared with bare metal stent treated patients (odds ratio, 0.92; confidence interval, 0.64- 1.33; p = 0.7; 6.7% versus 6.8% respectively). Prespecified separate analysis for randomised

In patients treated by drug-eluting stents a strong significant reduction of target vessel revascularisation compared with bare metal stent-treated patients was observed (odds ratio, 0.53; confidence interval, 0.39-0.72; p < 0.0001; 12.3% versus 18.8%). Drug-eluting stent advantage was comparable and statistically significant for both randomised and nonrandomised studies. The prespecified meta-regression analysis showed an advantage for drug-eluting stents in diabetic patients (p =0.03) and in percutaneous graft intervention performed with embolic protection devices (p = 0.04); reduction of target vessel revascularisation with dug-eluting stent use was directly proportional to saphenous vein

This meta-analysis supports the use of drug-eluting stents to reduce target vessel revascularisation in patients with saphenous vein graft disease. However, in this patient population, clear benefits from the use of drug-eluting stents in the reduction of death and

Another recent and large meta-analysis by Hakeem et al included 2 randomised trials, one subgroup analysis from a randomised trial and 26 observational studies comparing drugeluting stents with bare metal stents for saphenous vein graft lesions comprising a total of

treatment of saphenous vein graft disease have been published.

with follow-up period longer than 6 months.

and non-randomised studies yielded similar results.

myocardial infarction were not observed (Lupi et al., 2011).

after stenting. Clopidogrel was initially recommended for 6 months after paclitaxel-eluting stent placement and for at least one month after bare metal stent placement. Since December 2006 (patients were enrolled between 2005 and 2007), a minimum of one year of clopidogrel was recommended after paclitaxel-eluting stent placement. Primary stenting was used in most lesions. Procedural success was achieved in 96% of the patients.

Binary angiographic restenosis occurred in 51% of the bare metal stent-treated lesions versus 9% of the paclitaxel-eluting stent-treated lesions (relative risk: 0.18; 95% confidence interval: 0.07 to 0.48, p < 0.0001). During a median follow-up of 1.5 years the paclitaxeleluting stent patients had less target lesion revascularisation (28% versus 5%, hazard ratio: 0.38; 95% confidence interval: 0.15 to 0.74, p = 0.003) and less target vessel failure defined as the composite end point of cardiac death, myocardial infarction and target vessel revascularisation (46% versus 22%, hazard ratio 0.65; 95% confidence interval: 0.42 to 0.96, p = 0.03). There were trends toward fewer myocardial infarctions (31% versus 15%, hazard ratio: 0.67; 95% confidence interval: 0.40 to 1.08, p = 0.10) and less target vessel revascularisation (31% versus 15%, hazard ratio: 0.66; 95% confidence interval: 0.39 to 1.05, p =0.08) in paclitaxel eluting stent patients (Brilakis et al., 2009). An important finding of this 80-patient study was that all-cause mortality was similar between the 2 groups at a median follow-up of 1.5 years (Bittl, 2009; Brilakis et al., 2009). This study was limited by the relatively small number of patients and was underpowered to detect differences in clinical outcome (Brilakis et al., 2009).

In summary, the use of paclitaxel-eluting stents in saphenous vein graft lesions in the SOS trial was associated with lower rates of angiographic restenosis and target vessel failure than bare metal stents. The median follow-up of patients in this trial was 1.5 years; it is unknown whether the outcomes would change with longer-term follow-up.

The ISAR-CABG (Is Drug-Eluting Stenting Associated with Improved Results in Coronary Artery Bypass Grafts) trial randomized 610 patients with de novo lesions in saphenous vein grafts to receive either a drug-eluting stent (n=303) or a bare metal stent (n=307). Patients in the drug-eluting sent group received a paclitaxel-eluting, sirolimus-eluting, or bio-absorbable polymer sirolimus-eluting stent. The average age of the saphenous vein grafts was 13 years. The primary endpoint was a composite of major adverse cardiac events (death, myocardial infarction, or target lesion revascularization at 1-year followup).

At one-year post intervention the incidence of major adverse cardiac events was reduced by 35% in the drug-eluting stent cohort compared to the bare metal stent group (15.4% versus 22.1%, p = 0.03). The difference was almost entirely driven by a nearly 50% relative reduction in the risk of target lesion revascularization (7.2% versus 13.1%, p= 0.02). There were no statistically significant differences in the individual rates of death or myocardial infarction (Mehilli et al., 2011).

Two ongoing trials are comparing drug-eluting stents with bare metal stents in saphenous vein grafts; the BASKETSAVAGE (Basel Stent Kosten Effektivitäts Trial-Saphenous Venous Graft Angioplasty Using Glycoprotein IIb/IIIa Receptor Inhibitors and Drug-Eluting Stents) (NCT00595647); and the Veterans Affairs Cooperative Study # 571, DIVA (Drug-Eluting Stents Versus Bare Metal Stents in Saphenous Vein Graft Angioplasty) trials (NCT01121224) (Lee et al., 2011).

The results of randomised trials of drug-eluting stents in saphenous vein grafts can not be extrapolated to large saphenous vein grafts (with a reference vessel diameter > 4.0 mm) or to totally occluded vein grafts because they were excluded from randomisation in those studies.

#### **8.2 Meta-analysis**

108 Coronary Interventions

after stenting. Clopidogrel was initially recommended for 6 months after paclitaxel-eluting stent placement and for at least one month after bare metal stent placement. Since December 2006 (patients were enrolled between 2005 and 2007), a minimum of one year of clopidogrel was recommended after paclitaxel-eluting stent placement. Primary stenting was used in

Binary angiographic restenosis occurred in 51% of the bare metal stent-treated lesions versus 9% of the paclitaxel-eluting stent-treated lesions (relative risk: 0.18; 95% confidence interval: 0.07 to 0.48, p < 0.0001). During a median follow-up of 1.5 years the paclitaxeleluting stent patients had less target lesion revascularisation (28% versus 5%, hazard ratio: 0.38; 95% confidence interval: 0.15 to 0.74, p = 0.003) and less target vessel failure defined as the composite end point of cardiac death, myocardial infarction and target vessel revascularisation (46% versus 22%, hazard ratio 0.65; 95% confidence interval: 0.42 to 0.96, p = 0.03). There were trends toward fewer myocardial infarctions (31% versus 15%, hazard ratio: 0.67; 95% confidence interval: 0.40 to 1.08, p = 0.10) and less target vessel revascularisation (31% versus 15%, hazard ratio: 0.66; 95% confidence interval: 0.39 to 1.05, p =0.08) in paclitaxel eluting stent patients (Brilakis et al., 2009). An important finding of this 80-patient study was that all-cause mortality was similar between the 2 groups at a median follow-up of 1.5 years (Bittl, 2009; Brilakis et al., 2009). This study was limited by the relatively small number of patients and was underpowered to detect differences in clinical

In summary, the use of paclitaxel-eluting stents in saphenous vein graft lesions in the SOS trial was associated with lower rates of angiographic restenosis and target vessel failure than bare metal stents. The median follow-up of patients in this trial was 1.5 years; it is

The ISAR-CABG (Is Drug-Eluting Stenting Associated with Improved Results in Coronary Artery Bypass Grafts) trial randomized 610 patients with de novo lesions in saphenous vein grafts to receive either a drug-eluting stent (n=303) or a bare metal stent (n=307). Patients in the drug-eluting sent group received a paclitaxel-eluting, sirolimus-eluting, or bio-absorbable polymer sirolimus-eluting stent. The average age of the saphenous vein grafts was 13 years. The primary endpoint was a composite of major adverse cardiac events (death, myocardial infarction, or target lesion revascularization at 1-year follow-

At one-year post intervention the incidence of major adverse cardiac events was reduced by 35% in the drug-eluting stent cohort compared to the bare metal stent group (15.4% versus 22.1%, p = 0.03). The difference was almost entirely driven by a nearly 50% relative reduction in the risk of target lesion revascularization (7.2% versus 13.1%, p= 0.02). There were no statistically significant differences in the individual rates of death or myocardial

Two ongoing trials are comparing drug-eluting stents with bare metal stents in saphenous vein grafts; the BASKETSAVAGE (Basel Stent Kosten Effektivitäts Trial-Saphenous Venous Graft Angioplasty Using Glycoprotein IIb/IIIa Receptor Inhibitors and Drug-Eluting Stents) (NCT00595647); and the Veterans Affairs Cooperative Study # 571, DIVA (Drug-Eluting Stents Versus Bare Metal Stents in Saphenous Vein Graft Angioplasty) trials (NCT01121224)

unknown whether the outcomes would change with longer-term follow-up.

most lesions. Procedural success was achieved in 96% of the patients.

outcome (Brilakis et al., 2009).

infarction (Mehilli et al., 2011).

(Lee et al., 2011).

up).

Several meta-analysis including evidence from randomised trials and observational studies that compared the use of drug-eluting stents versus bare metal stents in the percutaneous treatment of saphenous vein graft disease have been published.

A meta-analysis by Lupi et al included 23 studies comparing drug-eluting stents versus bare metal stents enrolling a total of 7,090 patients with saphenous vein graft disease. Three of the 23 studies included in this meta-analysis were randomised controlled trials and the remaining 20 were non-randomised studies. These authors included in their meta-analysis randomised and/or non-randomised studies, studies reporting clinical outcomes as overall death and/or acute myocardial infarction and/or target vessel revascularisation and studies with follow-up period longer than 6 months.

Patients treated by drug-eluting stents showed lower overall mortality rates with marginal statistical significance compared with those treated by bare metal stents (odds ratio, 0.63; confidence interval, 0.40-0.99; p =0.05; 7.0% versus 15.3% respectively). Subgroup analysis revealed a difference in the outcome between randomised and non-randomised studies. In particular, a survival benefit following drug eluting stent implantation was observed in nonrandomised studies (odds ratio, 0.57; confidence interval, 0.36-0.90; p=0.02), but not in randomised controlled trials (odds ratio, 2.23; confidence interval, 0.15-32.35; p=0.56).

Patients treated by drug-eluting stents showed no benefit in myocardial infarction rates compared with bare metal stent treated patients (odds ratio, 0.92; confidence interval, 0.64- 1.33; p = 0.7; 6.7% versus 6.8% respectively). Prespecified separate analysis for randomised and non-randomised studies yielded similar results.

In patients treated by drug-eluting stents a strong significant reduction of target vessel revascularisation compared with bare metal stent-treated patients was observed (odds ratio, 0.53; confidence interval, 0.39-0.72; p < 0.0001; 12.3% versus 18.8%). Drug-eluting stent advantage was comparable and statistically significant for both randomised and nonrandomised studies. The prespecified meta-regression analysis showed an advantage for drug-eluting stents in diabetic patients (p =0.03) and in percutaneous graft intervention performed with embolic protection devices (p = 0.04); reduction of target vessel revascularisation with dug-eluting stent use was directly proportional to saphenous vein graft age (p = 0.005).

This meta-analysis supports the use of drug-eluting stents to reduce target vessel revascularisation in patients with saphenous vein graft disease. However, in this patient population, clear benefits from the use of drug-eluting stents in the reduction of death and myocardial infarction were not observed (Lupi et al., 2011).

Another recent and large meta-analysis by Hakeem et al included 2 randomised trials, one subgroup analysis from a randomised trial and 26 observational studies comparing drugeluting stents with bare metal stents for saphenous vein graft lesions comprising a total of

Percutaneous Intervention Post Coronary

respectively) and death (7.4% versus 2%).

increasing filter efficiency (Roffi et al., 2002).

among many causes of no-reflow (Habibzadeh et al., 2011).

Artery Graft Surgery in Patients with Saphenous Vein Graft Disease – State of the Art 111

neutrophils activation and interaction with endothelium, distal embolisation of plaque and/or thrombus, local release of vasoconstrictor substances have been thought to be

As expected, no-reflow is associated with worse clinical outcomes including post-procedural myocardial infarction (17.7% versus 3.5%in patients with and without no-reflow,

Various techniques, both interventional and pharmacological, have been used in the treatment of no-reflow. Covered stents, as already discussed, were thought to inhibit distal embolisation by sequestering friable atheroemboli; however, this hypothesis seems to have been invalidated. Clinical trials of the routine use of glycoprotein IIb/IIIa receptor blockers during percutaneous intervention of saphenous vein grafts have shown no benefit for the reduction of major adverse cardiac events (Carter et al., 2007). A pooled analysis of 5 randomised intravenous glycoprotein IIb/IIIa inhibitor trials assessed the outcomes of graft interventions at 30 days and 6 months. The study population consisted of 13,158 patients undergoing percutaneous treatment of native coronary arteries and 627 patients treated for by pass graft disease. Treatment assignment and complete follow-up data were available for 605 patients with graft intervention (96.5%). Among them 389 patients were randomised to IIb/IIIa integrin blockade (abciximab in 51% of cases and eptifibatide in 49% of cases) and 216 patients were allocated to placebo. The incidence of death myocardial infarction or urgent revascularization at 30 days was 16.5% among patients allocated to glycoprotein IIb/IIIa inhibitors and 12.6% among those receiving placebo (odds ratio 1.38; 96% confidence interval, 0.85 to 2.24; p = 0.18). At six months, the combined event rate of death, myocardial infarction or revascularisation was 39.4% and 32.7% (hazards ratio 1.29; 95% confidence interval, 0.97 to 1.72; p = 0.07), respectively. The incidence of major bleeding was 6.8% among graft percutaneous intervention patients randomised to platelet glycoprotein IIb/IIIa inhibitors and 1.4% among those allocated to placebo (p = 0.004). The corresponding incidences of minor bleeding were 14.9% versus 8.1% (p = 0.016) respectively. Accordingly, no benefit from IIb/IIIa integrin blockade was detected in terms of individual or combined end points either at 30 days or at 6 months in patients undergoing saphenous vein graft interventions. From a safety perspective, adjunctive glycoprotein IIb/IIIa receptor inhibition was associated with an increased incidence of major and minor bleedings (Roffi et al., 2002). The authors of this analysis stated that additional studies were needed to define whether the use of platelet glycoprotein IIb/IIIa receptor inhibitors in conjunction with embolic protection devices might improve outcomes. According to them profound platelet inhibition may have complementary beneficial effect in particular when associated with filter devices. In this regard, whereas the filter offers mechanical protection from larger particles, glycoprotein IIb/IIIa inhibitors could exert their beneficial effect on the microvasculature jeopardized from microparticles that escape the filters. In addition, the use of potent platelet inhibition may allow for reduced filter pore size by preventing filter thrombosis, thereby

The SAFER and FIRE trials established the safety an efficacy of balloon occlusion/aspiration (GuardWire) and filter-based (FilterWire) protection devices as useful adjuncts during saphenous vein grafts intervention. In both trials the use of glycoprotein IIb/IIIa inhibitors was at the discretion of the investigator, with randomisation stratified by intention to use glycoprotein IIb/IIIa blockade so that roughly equal numbers of patients in each arm would

7,994 patients (4,187 patients in the drug-eluting stent arm and 3,807 patients in the bare metal stent group). This meta-analysis reaffirmed the benefit of drug-eluting stents over bare metal stents in major adverse cardiac event reduction, which was primarily driven by lower revascularisation rates in the drug-eluting stent group. The observed drug-eluting stent benefit was largely based on the outcome of observational studies. Pooled analysis of all studies in this meta-analysis showed a mortality benefit associated with the use of drugeluting stents. However, for studies with 12 and 24 months of follow-up, there was no difference with respect to mortality between drug-eluting stents and bare metal stents. Hence, long-term use of drug-eluting stents was not associated with an increased risk of death. Target vessel revascularisation was 12% in drug-eluting stents compared with 17% in bare metal stents, with risk ratio of 0.71 (0.59, 0.85), p = 0.0002. This effect was sustained in studies with > 12 and > 24 months follow-up. This study observed a significant reduction in the risk of myocardial infarction with the use of drug-eluting stents compared with bare metal stents. Although there was no statistically significant difference in the incidence of stent thrombosis, there was a trend towards increased stent thrombosis in the bare metal stent group (1% in drug-eluting stents and 1.7% in bare metal stents with a risk ratio of 0.63 [0.36 - 1.11] p= 0.11). According to this authors, the use of drug-eluting stents in saphenous vein grafts appears to be safe both in the short term and long term as demonstrated primarily in observational nonrandomised studies.

Target vessel revascularization is the only outcome with consistent benefit from drugeluting stent versus bare metal stents in saphenous vein grafts in both randomised and observational data. While patients undergoing saphenous vein graft percutaneous intervention are at higher baseline risk, this "negative result" on myocardial infarction and death is consistent with the overall experience. Meta-analysis of all drug-eluting stent versus bare metal stent randomized controlled trials (n = 22 studies with 9740 patients) yields no significant reduction in death [OR = 0.97 (0.81 – 1.15)] or myocardial infarction [OR = 0.94 (0.78 – 1.13)] in those randomly assigned to drug eluting stents (Hillegass, 2011). There is clear-cut target vessel revascularisation benefit of drug-eluting stents in largely native vessels [OR = 0.45 (0.37 – 0.54), p <0.001]. Interestingly, the point estimate for reduction in target vessel revascularisation with drug-eluting stents in saphenous vein grafts is similar to native vessels. Over the longer term of 2 years, however, we remain with limited proof of a prolonged saphenous vein graft patency advantage with drug-eluting stents versus bare metal stents in well-controlled trials (Hillegass, 2011).

#### **9. No-reflow phenomenon a major complication during percutaneous intervention of saphenous vein grafts**

Distal embolisation of atheroemboli is a well-known consequence of saphenous vein grafts intervention and may result in diminished blood flow to the distal vascular bed resulting in peri-procedural ischaemia and infarction. This appropriately named "no-reflow" phenomenon occurs as a result of distal embolisation of atheroembolic debris (Carter et al., 2007). No-reflow is defined as the failure to restore normal coronary antegrade flow despite appropriate treatment of a coronary obstruction in the absence of dissection, thrombus formation or vessel closure.

The cause of no-reflow is complex and multifactorial. Various mechanisms like alphaadrenergic vascular constriction, local increase in angiotensin II receptor density,

7,994 patients (4,187 patients in the drug-eluting stent arm and 3,807 patients in the bare metal stent group). This meta-analysis reaffirmed the benefit of drug-eluting stents over bare metal stents in major adverse cardiac event reduction, which was primarily driven by lower revascularisation rates in the drug-eluting stent group. The observed drug-eluting stent benefit was largely based on the outcome of observational studies. Pooled analysis of all studies in this meta-analysis showed a mortality benefit associated with the use of drugeluting stents. However, for studies with 12 and 24 months of follow-up, there was no difference with respect to mortality between drug-eluting stents and bare metal stents. Hence, long-term use of drug-eluting stents was not associated with an increased risk of death. Target vessel revascularisation was 12% in drug-eluting stents compared with 17% in bare metal stents, with risk ratio of 0.71 (0.59, 0.85), p = 0.0002. This effect was sustained in studies with > 12 and > 24 months follow-up. This study observed a significant reduction in the risk of myocardial infarction with the use of drug-eluting stents compared with bare metal stents. Although there was no statistically significant difference in the incidence of stent thrombosis, there was a trend towards increased stent thrombosis in the bare metal stent group (1% in drug-eluting stents and 1.7% in bare metal stents with a risk ratio of 0.63 [0.36 - 1.11] p= 0.11). According to this authors, the use of drug-eluting stents in saphenous vein grafts appears to be safe both in the short term and long term as demonstrated

Target vessel revascularization is the only outcome with consistent benefit from drugeluting stent versus bare metal stents in saphenous vein grafts in both randomised and observational data. While patients undergoing saphenous vein graft percutaneous intervention are at higher baseline risk, this "negative result" on myocardial infarction and death is consistent with the overall experience. Meta-analysis of all drug-eluting stent versus bare metal stent randomized controlled trials (n = 22 studies with 9740 patients) yields no significant reduction in death [OR = 0.97 (0.81 – 1.15)] or myocardial infarction [OR = 0.94 (0.78 – 1.13)] in those randomly assigned to drug eluting stents (Hillegass, 2011). There is clear-cut target vessel revascularisation benefit of drug-eluting stents in largely native vessels [OR = 0.45 (0.37 – 0.54), p <0.001]. Interestingly, the point estimate for reduction in target vessel revascularisation with drug-eluting stents in saphenous vein grafts is similar to native vessels. Over the longer term of 2 years, however, we remain with limited proof of a prolonged saphenous vein graft patency advantage with drug-eluting stents versus bare

**9. No-reflow phenomenon a major complication during percutaneous**

Distal embolisation of atheroemboli is a well-known consequence of saphenous vein grafts intervention and may result in diminished blood flow to the distal vascular bed resulting in peri-procedural ischaemia and infarction. This appropriately named "no-reflow" phenomenon occurs as a result of distal embolisation of atheroembolic debris (Carter et al., 2007). No-reflow is defined as the failure to restore normal coronary antegrade flow despite appropriate treatment of a coronary obstruction in the absence of dissection, thrombus

The cause of no-reflow is complex and multifactorial. Various mechanisms like alphaadrenergic vascular constriction, local increase in angiotensin II receptor density,

primarily in observational nonrandomised studies.

metal stents in well-controlled trials (Hillegass, 2011).

**intervention of saphenous vein grafts**

formation or vessel closure.

neutrophils activation and interaction with endothelium, distal embolisation of plaque and/or thrombus, local release of vasoconstrictor substances have been thought to be among many causes of no-reflow (Habibzadeh et al., 2011).

As expected, no-reflow is associated with worse clinical outcomes including post-procedural myocardial infarction (17.7% versus 3.5%in patients with and without no-reflow, respectively) and death (7.4% versus 2%).

Various techniques, both interventional and pharmacological, have been used in the treatment of no-reflow. Covered stents, as already discussed, were thought to inhibit distal embolisation by sequestering friable atheroemboli; however, this hypothesis seems to have been invalidated. Clinical trials of the routine use of glycoprotein IIb/IIIa receptor blockers during percutaneous intervention of saphenous vein grafts have shown no benefit for the reduction of major adverse cardiac events (Carter et al., 2007). A pooled analysis of 5 randomised intravenous glycoprotein IIb/IIIa inhibitor trials assessed the outcomes of graft interventions at 30 days and 6 months. The study population consisted of 13,158 patients undergoing percutaneous treatment of native coronary arteries and 627 patients treated for by pass graft disease. Treatment assignment and complete follow-up data were available for 605 patients with graft intervention (96.5%). Among them 389 patients were randomised to IIb/IIIa integrin blockade (abciximab in 51% of cases and eptifibatide in 49% of cases) and 216 patients were allocated to placebo. The incidence of death myocardial infarction or urgent revascularization at 30 days was 16.5% among patients allocated to glycoprotein IIb/IIIa inhibitors and 12.6% among those receiving placebo (odds ratio 1.38; 96% confidence interval, 0.85 to 2.24; p = 0.18). At six months, the combined event rate of death, myocardial infarction or revascularisation was 39.4% and 32.7% (hazards ratio 1.29; 95% confidence interval, 0.97 to 1.72; p = 0.07), respectively. The incidence of major bleeding was 6.8% among graft percutaneous intervention patients randomised to platelet glycoprotein IIb/IIIa inhibitors and 1.4% among those allocated to placebo (p = 0.004). The corresponding incidences of minor bleeding were 14.9% versus 8.1% (p = 0.016) respectively. Accordingly, no benefit from IIb/IIIa integrin blockade was detected in terms of individual or combined end points either at 30 days or at 6 months in patients undergoing saphenous vein graft interventions. From a safety perspective, adjunctive glycoprotein IIb/IIIa receptor inhibition was associated with an increased incidence of major and minor bleedings (Roffi et al., 2002). The authors of this analysis stated that additional studies were needed to define whether the use of platelet glycoprotein IIb/IIIa receptor inhibitors in conjunction with embolic protection devices might improve outcomes. According to them profound platelet inhibition may have complementary beneficial effect in particular when associated with filter devices. In this regard, whereas the filter offers mechanical protection from larger particles, glycoprotein IIb/IIIa inhibitors could exert their beneficial effect on the microvasculature jeopardized from microparticles that escape the filters. In addition, the use of potent platelet inhibition may allow for reduced filter pore size by preventing filter thrombosis, thereby increasing filter efficiency (Roffi et al., 2002).

The SAFER and FIRE trials established the safety an efficacy of balloon occlusion/aspiration (GuardWire) and filter-based (FilterWire) protection devices as useful adjuncts during saphenous vein grafts intervention. In both trials the use of glycoprotein IIb/IIIa inhibitors was at the discretion of the investigator, with randomisation stratified by intention to use glycoprotein IIb/IIIa blockade so that roughly equal numbers of patients in each arm would

Percutaneous Intervention Post Coronary

measure alone (Habibzadeh et al., 2011).

**10.1 Distal balloon occlusion devices**

universally (Morís et al., 2009).

of antegrade flow (Figure 2).

(Fischell, 1998).

verapamil infusion.

Artery Graft Surgery in Patients with Saphenous Vein Graft Disease – State of the Art 113

out of the target vascular bed may act synergistically to reverse the no-reflow process

Intracoronary nicardipine has been shown to be the most potent vasodilator used for noreflow prevention. Intragraft administration of nicardipine can cause longer vasodilation with a lower risk of serious systemic side effects compared to intracoronary diltiazem or

In 2007, Fischell et al reported some promising results with the use of intracoronary nicardipine to prevent no-reflow without distal mechanical protection in saphenous vein graft intervention. They evaluated 83 saphenous vein grafts interventions involving 68 consecutive patients. All saphenous vein grafts lesions underwent successful stent placement. All patients received 200-300 µg of intragraft nicardipine (10-15 µg/ ml of normal saline) injected via the guiding catheter immediately prior to stenting (Habibzadeh et al., 2011). These authors showed favourable results with reduction in major adverse cardiac events comparable to that of the early distal protection trials (Carter et al., 2007).

Despite the increasing use of pharmacologic means to prevent no-reflow, distal embolic protection remains a vital component of therapy (Carter et al, 2007). It is of note; however, that despite the use of protection devices, significant no-reflow can occur during saphenous vein graft intervention. The no-reflow phenomenon might be predominantly caused by microvascular spasm and not directly by mechanical obstruction from distal embolisation (Habibzadeh et al., 2011). A combination of intragraft administration of nicardipine together with the use of protection devices has not been studied but appears to be logical, with significant potential to reduce the occurrence of no-reflow compared to each preventive

**10. Embolic protection devices during saphenous vein graft interventions**

There are two types of embolic protection devices: balloon occlusion-aspiration (proximal or distal) and filter devices. These systems have different characteristics and to date none has demonstrated enough advantages over the other mechanism to be ideally recommended

The Guard-Wire (Medtronic, Minneapolis, MN) temporary occlusion-aspiration system, consist of a wire with a central lumen that inflates an elastomeric balloon at the distal tip of the wire. The lesion is crossed with the Guard-Wire. Once the balloon is inflated (2.5 to 5.0 mm or 3.0 to 6.0 mm in diameter) with diluted contrast using an adaptor device, it occludes flow distal to the target lesion. The procedure (angioplasty and stenting) is then performed over the Guard-Wire shaft instead of using a standard angioplasty guidewire. Liberated plaque and thrombotic debris trapped proximal to the balloon are then aspirated through a 5 French monorail Export aspiration catheter. The balloon is then deflated with restoration

The SAFER (Saphenous vein graft Angioplasty Free of Emboli Randomized) trial enrolled 801 patients with signs of myocardial ischemia resulting from a target lesion > 50% diameter stenosis located in the mid-portion of a saphenous vein graft, with a reference vessel

be treated with glycoprotein IIb/IIIa inhibitors. In the SAFER trial patients pre-selected for IIb/IIIa treatment in both the GuardWire assigned and control (unprotected) arms had higher rates of major adverse cardiac events than those not treated with glycoprotein IIb/IIIa inhibitors; this observation is most likely due to selection of a higher-risk cohort to receive IIb/IIIa antagonists.

Jonas et al., studied the FIRE trial database to examine whether glycoprotein IIb/IIIa blockers would interact differently with the FilterWire EX and the GuardWire embolic protection devices. The principal findings of their report were that patients pre-selected for glycoprotein IIb/IIIa inhibitor therapy manifested higher risk baseline characteristics, greater procedural complexity and correspondingly higher overall 30-day major adverse cardiac event rates. They also had higher bleeding risk and required more transfusions. Among patients randomised to distal embolic protection with the GuardWire, major adverse cardiac events were higher with glycoprotein IIb/IIIa inhibitors than without. In contrast among patients randomised to the FilterWire, major adverse cardiac events were not higher with glycoprotein IIb/IIIa inhibitors than without. Glycoprotein IIb/IIIa inhibitor therapy was associated with superior FilterWire (but not GuardWire) performance, including better preservation of flow through the filter, reduced procedural ischaemia and reduced occurrence of abrupt closure, no reflow, or distal embolization (Jonas et al., 2005).

Intracoronary calcium channel blockers and the vasodilators adenosine and nitroprusside are commonly used in the treatment of no-reflow. Unfortunately this therapy is usually employed once the phenomenon has occurred (Carter et al., 2007).

Nitroprusside is a direct donor of nitric oxide that is a potent vasodilator in the resistance arteriolar circulation and plays a significant role in the control of coronary blood flow through the microcirculation. In a retrospective analysis of 20 percutaneous coronary interventions including 9 (45%) in saphenous vein grafts, intracoronary nitroprusside administered for no-reflow (median injection dose 200 µg) led to a rapid improvement in both angiographic flow (p<0.01 compared with pretreatment angiogram) and blood flow velocity (p<0.01 compared with pretreatment angiogram). No significant hypotension or other adverse clinical events were associated with nitroprusside administration (Hillegass, 2001).

Adenosine inhibits platelet activation, impedes platelet aggregation, and is a potent arteriolar dilator that has been shown to reduce the incidence of no-reflow following percutaneous coronary intervention in native vessels, and reverse but not prevent no-reflow in degenerated saphenous vein grafts. Intracoronary adenosine has an extremely short halflife and duration of action, and thus requires repetitive dosing during percutaneous coronary intervention (Fischell, 2008). In a small study, 8 patients who experienced 9 noreflow and 2 slow flow events complicating saphenous vein graft interventions were treated with the rapid and repeated injection of adenosine (average of 12.1 ± 3.4 boluses of adenosine per event, with 3-4 saline 3-ml flushes following each adenosine syringe bolus). All 11 no-reflow/slow-flow events were substantially improved within 7 minutes of treatment. Angiographically normal flow (TIMI 3) was achieved in 10 of 11 events (91%). These authors hypothesized that the combination of microvascular (arteriolar) vasodilatation by adenosine combined with forceful mechanical flushing of embolic debris

be treated with glycoprotein IIb/IIIa inhibitors. In the SAFER trial patients pre-selected for IIb/IIIa treatment in both the GuardWire assigned and control (unprotected) arms had higher rates of major adverse cardiac events than those not treated with glycoprotein IIb/IIIa inhibitors; this observation is most likely due to selection of a higher-risk cohort to

Jonas et al., studied the FIRE trial database to examine whether glycoprotein IIb/IIIa blockers would interact differently with the FilterWire EX and the GuardWire embolic protection devices. The principal findings of their report were that patients pre-selected for glycoprotein IIb/IIIa inhibitor therapy manifested higher risk baseline characteristics, greater procedural complexity and correspondingly higher overall 30-day major adverse cardiac event rates. They also had higher bleeding risk and required more transfusions. Among patients randomised to distal embolic protection with the GuardWire, major adverse cardiac events were higher with glycoprotein IIb/IIIa inhibitors than without. In contrast among patients randomised to the FilterWire, major adverse cardiac events were not higher with glycoprotein IIb/IIIa inhibitors than without. Glycoprotein IIb/IIIa inhibitor therapy was associated with superior FilterWire (but not GuardWire) performance, including better preservation of flow through the filter, reduced procedural ischaemia and reduced occurrence of abrupt closure, no reflow, or distal embolization

Intracoronary calcium channel blockers and the vasodilators adenosine and nitroprusside are commonly used in the treatment of no-reflow. Unfortunately this therapy is usually

Nitroprusside is a direct donor of nitric oxide that is a potent vasodilator in the resistance arteriolar circulation and plays a significant role in the control of coronary blood flow through the microcirculation. In a retrospective analysis of 20 percutaneous coronary interventions including 9 (45%) in saphenous vein grafts, intracoronary nitroprusside administered for no-reflow (median injection dose 200 µg) led to a rapid improvement in both angiographic flow (p<0.01 compared with pretreatment angiogram) and blood flow velocity (p<0.01 compared with pretreatment angiogram). No significant hypotension or other adverse clinical events were associated with nitroprusside administration (Hillegass,

Adenosine inhibits platelet activation, impedes platelet aggregation, and is a potent arteriolar dilator that has been shown to reduce the incidence of no-reflow following percutaneous coronary intervention in native vessels, and reverse but not prevent no-reflow in degenerated saphenous vein grafts. Intracoronary adenosine has an extremely short halflife and duration of action, and thus requires repetitive dosing during percutaneous coronary intervention (Fischell, 2008). In a small study, 8 patients who experienced 9 noreflow and 2 slow flow events complicating saphenous vein graft interventions were treated with the rapid and repeated injection of adenosine (average of 12.1 ± 3.4 boluses of adenosine per event, with 3-4 saline 3-ml flushes following each adenosine syringe bolus). All 11 no-reflow/slow-flow events were substantially improved within 7 minutes of treatment. Angiographically normal flow (TIMI 3) was achieved in 10 of 11 events (91%). These authors hypothesized that the combination of microvascular (arteriolar) vasodilatation by adenosine combined with forceful mechanical flushing of embolic debris

employed once the phenomenon has occurred (Carter et al., 2007).

receive IIb/IIIa antagonists.

(Jonas et al., 2005).

2001).

out of the target vascular bed may act synergistically to reverse the no-reflow process (Fischell, 1998).

Intracoronary nicardipine has been shown to be the most potent vasodilator used for noreflow prevention. Intragraft administration of nicardipine can cause longer vasodilation with a lower risk of serious systemic side effects compared to intracoronary diltiazem or verapamil infusion.

In 2007, Fischell et al reported some promising results with the use of intracoronary nicardipine to prevent no-reflow without distal mechanical protection in saphenous vein graft intervention. They evaluated 83 saphenous vein grafts interventions involving 68 consecutive patients. All saphenous vein grafts lesions underwent successful stent placement. All patients received 200-300 µg of intragraft nicardipine (10-15 µg/ ml of normal saline) injected via the guiding catheter immediately prior to stenting (Habibzadeh et al., 2011). These authors showed favourable results with reduction in major adverse cardiac events comparable to that of the early distal protection trials (Carter et al., 2007).

Despite the increasing use of pharmacologic means to prevent no-reflow, distal embolic protection remains a vital component of therapy (Carter et al, 2007). It is of note; however, that despite the use of protection devices, significant no-reflow can occur during saphenous vein graft intervention. The no-reflow phenomenon might be predominantly caused by microvascular spasm and not directly by mechanical obstruction from distal embolisation (Habibzadeh et al., 2011). A combination of intragraft administration of nicardipine together with the use of protection devices has not been studied but appears to be logical, with significant potential to reduce the occurrence of no-reflow compared to each preventive measure alone (Habibzadeh et al., 2011).