Positive results for sirolimus-eluting stents in treating CLI

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Despite successful application of drug-eluting stents in the coronary arteries, there is limited data on their use in treating peripheral artery disease. However, two recent studies have demonstrated that infrapopliteal application of sirolimus-eluting stents (Cordis) for the treatment of critical limb ischaemia (CLI) attains good results in terms of low restenosis rates and repeat endovascular procedures in the first year after treatment.

At the recent EuroPCR meeting in Barcelona held from May 22-25 2007 and also featured in the Journal of Endovascular Therapy (2007:14;241-250), Dr. Konstantinos Katsanos, Department of Radiology, University of Patras, Rion, Greece, presented a study conducted under the leadership of Professor Dimitris Siablis and entitled ‘sirolimus-eluting versus bare metal stents after suboptimal infrapopliteal angioplasty for critical limb ischemia: enduring one-year angiographic and clinical benefit’.

According to Katsanos, the purpose of the study was to report the extended one-year angiographic and clinical results from a single-centre study that originally evaluated the provisional application of sirolimus-eluting or bare metal stents in the infrapopliteal arteries in patients with CLI.

Study procedure

The study was a prospective, non-randomised, single-centre, controlled, double-arm study investigating the hypothesis that ‘sirolumus-eluting stents are more effective than bare metal stents in inhibiting neointimal hyperplasia in the tibial arteries and improving angiographic and clinical outcome after suboptimal intrapopliteal angioplasty in patients suffering from CLI’. As outlined by Katsanos, because the majority of CLI patients suffer from diffuse infrapopliteal arterial obstructive disease requiring long angioplasty procedures, stenting was elected as a bailout procedure in case of suboptimal and/or complicated balloon angioplasty.

It was also reported that antiplatelet therapy (75mg/d clopidrogel and 100mg/d aspirin) was continued for six months after the intervention (unless the patients were taking warfarin).

Endpoints and follow-up

Katsanos explained that, “The primary clinical endpoints included target lesion reintervention [TLR], mortality, limb salvage, and minor amputation.” He also stated that primary patency was defined as the depiction of a non-occluded stented lesion without having undergone any additional intervention in or at the margins of the stented lesion. Binary in-stent restenosis was defined as narrowing of the in-stent lumen by >50% of the vessel diameter whereas binary in-segment restenosis evaluated an additional 0.5cm vessel margin proximal and distal to the stents with the >50% criterion. Follow-up included clinical and angiographic examination with intra-arterial digital subtraction angiography (DSA) at six months and one year.

Patient population and six-month results

Twenty-nine (29) patients were enrolled in each arm of the study, usually by alternating between the two stents types, said Dr. Katsanos. However, the sirolimus-eluting stents were occasionally unavailable, which impacted stent selection. Bare metal stents were deployed in 65 lesions (27 occlusions and 38 stenoses, median length 1.3cm) in 40 arteries of 29 limbs (group B), while 66 lesions (20 occlusions and 46 stenoses, median length 1.4cm) were treated with sirolimus-eluting stents in 41 arteries of 29 limbs (group S).

It was reported that baseline demographic variables were similar between the groups, with the exception of hyperlipidemia and symptomatic cardiac and carotid disease, which were significantly more prevalent in group S. Technical success of restoring at least 1 straight line of blood flow to the distal foot was 96.6% (28/29) in group B and 100% in group S on an intention-to-treat basis (p=0.17).

At six months, the numbers of patients with angiographic follow-up were comparable between the groups, i.e., 72.4% (21/29) in group B versus 75.9% (22/29) in group S, explained Katsanos. On a lesion basis, angiographic follow-up was available in 72.3% (47/65) of the bare metal stents and 75.8% (50/66) of the sirolumus-eluting stents (p=0.33).

Six-month primary patency was 68.1% in group B versus 92.0% in group S (p=0.0015). Binary in-stent and in-segment restenosis rates were 55.3% and 66.0% respectively, in patients with bare metal stents versus 4.0% and 32.0%, respectively, in patients treated with the sirolimus-eluting stents (both p<0.001). One-year results

At one-year, the proportion of patients undergoing one-year angiographic follow-up was similar in both groups, (68.9% in group B and 62.1% in group S). Katsanos revealed that one-year angiographic follow-up was available in 64.6% of the lesions treated with bare metal stents and 66.7% of the lesions in which sirolimus-eluting stents were deployed. The one-year primary patency rate was 40.5% in group B versus 86.4% in group S (p<0.001). Furthermore, the binary in-stent restenosis rate was 78.6% in group B versus 36.7% in group S (p<0.001). The authors of the study reported that restenosis (>50%) of the inflow femoropopliteal axis was recorded in 75.0% of the patients of group B and 66.7% of the patients of group S, with inflow axis reintervention performed in eight patients of group B and seven of group S. The study also showed that target lesion reintervention (TLR) rates at six months were 17.0% in group B versus 4.0% in group S (p=0.02), and limb salvage was 100% in both groups. Six-month mortality and minor amputation rates were 6.9% and 17.2%, respectively, in group B versus 10.3% and 3.4%, respectively, in group S.

After one year, it was found that the TLR rate was 26.2% in group B versus 9.1% in group S (p=0.02). All below-the-knee TLR cases of both groups were combined with concomitant femoropopliteal inflow repeat procedures. Limb salvage was 100% in group B and 96% in group S; a major amputation was necessary in one patient from the sirolimus group about eight months after the initial procedure (following occlusion of two stented lesions and progression of diffuse disease prohibiting invasive treatment).

Subgroup analysis on the basis of lesion grade (occlusions and stenoses) or diabetes showed primary patency to be significantly lower in all patients who had been treated with sirolimus-eluting stents (p<0.05). In addition, it was reported that after binary logistic regression analysis adjusted for diabetes, elevated creatinine, initial lesion grade, and stent type (bare metal or sirolimus-eluting), infrapopliteal sirolimus-eluting stents were found to be the sole independent predictor of significantly higher six-month primary patency, decreased restenosis and decreased TLR events both at six months and one year. Conclusion

To surmise, Katsanos explained that sirolimus-eluting stents exhibited enduring angiographic and clinical benefit compared with bare metal stents, with a high primary patency rate that was more than double the rate observed in bare metal stents. Patients treated with sirolimus-eluting stents also had fewer clinically-driven reinterventions, less than half the number with bare metal stents. “Arguably, we saw a trend toward increasing restenosis both within the stented area and at the edges for both bare and sirolimus stents, indicating the progressive nature of restenosis in the tibial vessels of CLI patients,” explained Katsanos.

With regard to mortality, limb salvage, and minor amputations, the study demonstrated that there were no significant differences between the groups at one year. Overall mortality was 12%, and one major amputation occurred in group S.

The authors also showed that the provisional application of sirolimus-eluting stents was associated with significantly fewer reinterventions driven by CLI relapse, which, according to the authors, reflects the beneficial clinical impact of reduced restenosis and underlies the value of not only restoring but also maintaining improved patency of the infrapopliteal arteries.

It was finally stated that large-scale multi-centre randomised trials with long-term follow-up are necessary to validate the results of the study and also to further investigate and compare the emerging infrapopliteal revascularisation technologies with traditional balloon angioplasty and surgical bypass.

Sirolimus-eluting stents in a tibial setting

Separately, in a study presented at the SIR meeting, Dr R A Lookstein, Mount Sinai Medical Center, NY, assessed whether technology currently employed to treat coronary artery disease could be applied to the tibial circulation.

Over a period of 18 months, a total of 20 patients underwent implantation of sirolimus-eluting stents to treat a suboptimal angioplasty result in a tibial vessel. All patients displayed symptoms of CLI and angiographic, clinical and non-invasive vascular examination results were collected prospectively.

The results showed that 29 stents were placed in 20 patients to treat a total of 25 angiographic lesions. A total of eight patients underwent simultaneous femoral-popliteal intervention. Initial technical success was 100%, with all 25 lesions being treated successfully with less than 10% stenosis after stent implantation.

At six months, clinical follow-up was available for 13 patients and there were two minor amputations and two major amputations. It was reported that there were three deaths in the cohort.

At 12-month follow-up, 4/5 patients had patent stents at duplex sonography. One patent with in-stent stenosis was noted to have a stent fracture upon examination with plain film radiograph.

Lookstein explained that although this is a relatively small study, early experience demonstrates that sirolimus-eluting stents are an effective therapy following suboptimal angioplasty in the setting of CLI, with excellent technical success and patency at follow-up.

Belgium experience

There were also numerous calls for stenting of the tibial arteries to become the firstline of treatment for CLI. On such presentation was from Dr Marc Bosiers, Belgium, began by stating that conservative treatment of CLI (Rutherford 5) has a 25% amputation rate after one year (JH Wolfe et al. Eur J Vasc Endovasc Surg. 1997;13:578-582), whereas surgical runs the risk of infection. He said that as a result endovascular intervention was the standard of care in his own institution as there were lower morbidity and mortality rates, limb salvage rates equally to surgical procedures and no prohibition of future bypass.

The issue of which stent to use is imperative and Bosiers explained that self-expanding nitinol stents are indicated for longer lesions, balloon expandable bare and coated stents present issues of crushing and adaptability, therefore he discussed his experience with the balloon expandable absorbable stent (Lekton Magic Explorer, Biotronik). He surmised that in his experience, for patients with CLI endovascular intervention is the first treatment of choice below the knee limb salvage and that the results using stenting will continue to improve as materials/stent designs are enhanced.

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