Effectiveness of the Sirolimus-Eluting Stent in the Treatment of Saphenous Vein Graft Disease

ABSTRACT: The use of bare stents for the percutaneous intervention of saphenous vein bypass grafts (SVGs) is associated with a high subsequent rate of restenosis. To assess the impact of the sirolimus-eluting stent (SES), we studied 19 consecutive patients who underwent de novo SVG intervention treated solely with SES. Mean graft age was 10 years. Clinical presentation was an acute coronary syndrome in 68%. In total, twenty-two de novo lesions were treated with 35 SESs (mean, 1.6 stents per lesion). Use of glycoprotein IIb/IIIa inhibitor therapy and distal embolization protection device were at operator discretion and were 42% and 32%, respectively. The rate of in-hospital major adverse cardiac events (MACE) was 11%, related to 2 patients with a creatine kinase rise consistent with peri-procedural acute myocardial infarction (AMI); a distal protection device was not utilized in either. Over a mean 12.5 ± 2.6 month follow-up, one patient died from a non-cardiac cause, and there were no further AMIs. Target lesion revascularization was undertaken in 1 patient (5%); survival free of MACE was 84%. In conclusion, utilizing SESs for percutaneous intervention of degenerate SVGs is associated with a low rate of target vessel revascularization. Increased utilization of distal protection devices might reduce the peri-procedural rate of AMI. J INVAS CARDIOL 2004;16:230–233 Key words: venous bypass graft, drug-eluting stents, angioplasty Coronary artery bypass grafting (CABG) is not a definitive therapy and patients continue to have considerable cardiovascular morbidity and mortality. Recurrence of angina occurs in 5–10% of patients each year, related to either progression of native vessel atherosclerosis or failure of the bypass grafts.¹ Indeed, angiographic studies have shown that by 10–12 years, 75–79% of saphenous vein grafts (SVGs) are occluded or severely diseased.^2,3 Revascularization with repeat CABG surgery is associated with increased mortality than a first operation, and less symptomatic improvement.^4,5 Percutaneous revascularization is therefore an attractive alternative strategy. However, although stent implantation is superior to balloon-alone angioplasty, follow-up shows a high 6-month restenosis rate of 37–53%.^6,7 Drug-eluting stents have been shown to be highly successful in reducing restenosis in native coronary disease in a select patient population.^8–10 This study evaluates the sirolimus-eluting stent (SES) in a high-risk population of patients undergoing intervention in diseased SVGs. Methods From April 2002, all percutaneous coronary interventions (PCIs) at our center were done with a policy of SES usage, irrespective of clinical presentation or lesion morphology. Further details of the methodology are described elsewhere.¹¹ The present study population is comprised of a consecutive series of 19 patients who underwent de novo SVG intervention with SESs. The maximum SES diameter available was 3.0 mm; therefore, at operator discretion, some additional patients (n = 8) with large diameter vein grafts were treated with at least one bare stent during the same study period and have been excluded from this analysis. The present cohort was treated with long-term aspirin therapy and received a loading dose of 300 mg clopidogrel followed by a daily dose of 75 mg for 6 months. The procedural utilization of glycoprotein IIb/IIIa inhibitor therapy and distal protection devices was at operator discretion. All patients signed written informed consent. Patients were followed prospectively and evaluated for survival free of major adverse cardiac events (MACE) pre-defined as: 1) death; 2) myocardial infarction (MI); or 3) repeat target vessel revascularization. The diagnosis of MI required an elevation of creatine kinase to twice the upper limit of normal, together with a rise in creatine kinase-MB fraction. Target lesion revascularization (TLR) was defined as either surgical or percutaneous reintervention driven by significant (> 50%) luminal narrowing either within the stent or the 5 mm borders proximal and distal to the stent, and was undertaken in the presence of either anginal symptoms or objective evidence of ischemia. Target vessel revascularization (TVR) was defined as reintervention in the treated vessel outside the target lesion. Angiographic success was defined as a post-procedural diameter stenosis of = 0.5 mm diameter greater than the stent was carried out in 25 of the 35 stents (71%). Angiographic success was achieved in all but 1 patient, in whom baseline TIMI 0 flow improved to a final TIMI II flow. The rate of in-hospital MACE was 11%, related to 2 patients with a peri-procedural acute MI (Table 3). Maximum level of creatine kinase in these two patients was 1,310 u/L and 579 u/L. Both were treated for an acute coronary syndrome, and neither had a distal protection device utilized. The patient with a Q-wave MI had an occluded graft at baseline, which was successfully recanalized and stented with three 33 mm-long stents. He was transferred to another hospital and subsequently had prolonged chest pain associated with ST-elevation on the electrocardiogram. This was medically managed and he was not referred back to our institution for further intervention. At a mean of 12.5 ± 2.6 months follow-up, there was 1 death and 1 patient underwent TLR, giving an overall survival rate free of MACE of 84% (Table 3). The patient who died was on dialysis for chronic renal failure. He had follow-up angiography 6 months after the index procedure, which confirmed that the graft was widely patent with no evidence of restenosis. His subsequent death 10.8 months after the index procedure followed a prolonged period of hospitalization and was felt to be non-cardiac. TLR was required by 1 patient (5%). This was the same patient with an in-hospital Q-wave MI. He underwent follow-up angiography at 6 months and the graft was found to be reoccluded at the ostium. Subsequent percutaneous intervention was unsuccessful, and he was discharged on medical therapy. Discussion More than half a million CABG operations are performed every year in the United States alone, meaning an increasing number of patients are developing recurrent ischemia and angina. In the large Coronary Artery Surgery Study (CASS) of more than 9,500 patients, angina recurred in 24% within the first year and in 40% by the sixth year.¹² Revascularization with a second or third bypass operation is technically more difficult and associated with less symptomatic improvement and increased operative mortality compared with a first CABG.^4,5 Recent data suggest a mortality for reoperation of 4.2%;¹³ however, much of the published data regarding mortality and morbidity in this population relate to a selected group of relatively lower risk patients. Results cannot therefore be generally applied to the whole population of patients with a history of bypass surgery, many of whom will be older and have important comorbidity. Percutaneous revascularization for SVGs is an attractive, less invasive alternative strategy. However, results of balloon-only therapy were disappointing.^14–16 In one study of 454 patients, procedural success was 90% with a 5-year MACE-free survival of just 26%.¹⁶ Stenting improves outcomes both by reducing restenosis and stabilizing friable material within venous grafts, thus reducing the risk of distal embolization. A randomized trial of stenting versus balloon-only angioplasty showed that at 6-month follow-up, the stented group had a higher rate of freedom from death, AMI, repeat CABG or TLR (73% versus 58%, respectively; p = 0.03).⁷ However, the angiographic restenosis rate remained high (37% versus 46%, respectively; p = 0.24). Importantly, complex SVG lesions, such as long lesions (requiring more than one 15-mm long stent) and stenoses at the anastomotic site, were excluded. In our study, a higher-risk unselected population was evaluated; indeed, sixteen of our patients (84%) would have been excluded from the above study. Yet our results are favorable (Figure 1); MACE-free rate is 84% and TLR rate is 5% at just over 1 year of follow-up. In addition, studies have shown that the older the graft (> 3–5 years), the higher the rate of both restenosis and procedural complications.^14–17 The mean age of the grafts treated in the present study was 10 years (range, 9 months to 20 years); thus, the vast majority were at an increased risk for restenosis, and were likely to contain friable material at risk of embolization into the distal coronary bed. Direct stenting can reduce the occurrence of no-reflow,¹⁸ and we have shown that the SES performs well, with a high rate of successful direct stenting (82%). There were two patients with an in-hospital rise in creatine kinase consistent with MI. It is unlikely that this complication was specifically related to the use of an SES. No distal protection devices were used in these cases, although evidence suggests that this complication might have been avoided with such a device.^19,20 Indeed, our MI rate is highly comparable to those of published trials where bare metal stents were used, such as the SAFER study, where the 30-day rate was 16.5% in those treated conventionally, compared with 9.6% in those treated utilizing a distal protection device.²⁰ The maximum diameter of SES available during the study period was 3.0 mm, which is often small for a vein graft. Post-dilatation with either a 3.5 mm or 4.0 mm balloon was done in 71% of stents, and may have an effect on the therapeutic properties of elution with the theoretical potential for a reduction in benefit. This might relate to possible cracking of the polymer, or a relative decrease in dosage of drug as the struts are spread farther apart than intended for the stent design. Further studies are needed to assess whether this theoretical problem is of clinical significance; however, the future availability of stents with larger diameters will negate this. The major cause of an adverse cardiac event following percutaneous intervention in SVGs is restenosis, with reported 6-month rates between 37–53%.^6,7 Results of the SES for reduction of restenosis compared with bare stents in relatively simple lesions in native vessels have been extremely encouraging.^8–10 Pathological study of in-stent restenosis within SVGs has shown evidence of inflammation around the stent struts even months or years after implantation.²¹ It is hoped that the anti-inflammatory effects of agents such as sirolimus might thereby reduce subsequent restenosis. Study limitations. The present study reflects the “real world” of PCI in a high-risk group of patients, most treated in the setting of an acute coronary syndrome, and with grafts more than 5 years old. This initial study is limited by its small number and results cannot necessarily be extrapolated to those patients who were excluded from our study because of a large graft diameter requiring the use of a bare metal stent (maximum available diameter of SES was 3.0 mm). In addition, the present study is limited by the lack of routine angiographic follow-up. Patients were only asked back for control angiography at operator discretion, because they were felt to have had a complex index procedure. As such, only 5 of the 19 patients (26%) underwent scheduled follow-up angiography at 6 months. Despite these limitations, our preliminary data suggest that the use of SESs in SVG intervention is safe, with a peri-procedural complication rate comparable to conventional percutaneous techniques. At 12.5 ± 2.6 months, results of MACE-free survival (84%) and need for TLR (5%) were very encouraging. Further evaluation in the context of a larger randomized trial is warranted to confirm these results and the impact of the sirolimus-eluting stent in this high-risk population.