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Sirolimus for below the knee lesions: Mid-term results of SiroBTK study

Philippe Commeau, MD, FSCAI *, Paul Barragan, MD, Pierre O. Roquebert, MD
Département de Cardiologie et Radiologie Vasculaire Interventionelles, Polyclinique Les Fleurs, 83190 Ollioules, France

Introduction

Critical limb ischemia (CLI) represents a major challenge for all healthcare specialists involved in the treatment of this complex disease. CLI occurs when blood flow to the legs is severely diminished and is the end result following progressive obstructive atherosclerosis, most closely associated with the infra-popliteal arteries. It has been estimated that 1% of all adults over the age of 50-years suffer from CLI [[1-4]]. This figure equates to a potential patient population of between 1.5 and 2.0 million CLI patients in Europe and the USA [[5]].

Arterial revascularization with restoration of straight-line, pulsatile arterial blood flow is the major therapeutic goal to achieve a relief of rest pain and to facilitate wound healing. For many patients, surgical techniques are not applicable because of the general medical condition of this multi-diseased patient cohort. Furthermore, the lack of suitable distal outflow vessels or the absence of venous graft material can preclude surgical bypass grafting.

Recent advances in endovascular therapy including new wire technologies, low profile peripheral balloons as well as laser, cryotherapy, and atherectomy techniques have lead to an increasing use of interventional techniques for restoration of blood flow. Although the results of interventional therapy are generally promising, the occurrence of restenosis and reocclusions may result in insufficient clinical improvement. Endovascular stenting using balloon-expandable coronary stents has been shown to be of potential value to improve the results of infrapopliteal angioplasty [[6][7]]. Nevertheless, reobstruction rates of coronary bare-metal stents are in the range of 50-60% after 6 months [[1]]. Considering this reobstruction rate, the currently available evidence on the use of drug-eluting stents in coronary artery disease suggests that this new technology could be of major benefit for the treatment of patients with CLI [[8]].

Sirolimus (rapamycin) is a cytostatic macrocyclic lactone with both anti-inflammatory and anti-proliferative properties. Sirolimus, delivered from a polymer-encapsulated stent, can significantly reduce restenosis and thus improve the effectiveness of the stent. The sirolimus-eluting stent (SES) has been reported to be effective in de novo coronary lesions, with a substantial reduction in clinical and angiographic restenosis rates compared to conventional stents. The latest evidence suggests that SESs are also effective in the treatment of more complex lesions.

The objectives of the present study were to establish the safety and efficacy of the SES in the treatment of patients with infrapopliteal artery disease. Patients were followed up for an average of 7.7 months (range 2.0-24.0 months).

Materials and methods

Study Design and Patient Eligibility

The sirolimus for below the knee lesions (SiroBTK) study is a prospective, open, nonrandomized, single-arm registry. From June 2002 to September 2005, 30 patients with symptomatic infrapopliteal artery disease, confirmed as severe intermittent claudication or CLI, were treated with SES. Patients were followed up for an average of 7.7 months (range 2.0-24.0 months). All patients gave written informed consent for the procedure. The study was performed in accordance with Good Clinical Practice guidelines and the latest Declaration of Helsinki.

Severe intermittent claudication or CLI was defined as: (1) Category 3-6 of the Rutherford classification and (2) multiple lesions 2 vessel disease including the tibioperoneal trunk or 2 of anterior and posterior tibial and peroneal vessels, with or without lesions in the inferior segment of the popliteal artery (i.e. below-the-knee). Patients with existing restenosis, graft lesions, and with a lifetime expectancy of less than 1 year were excluded. This was also true for patients with an allergy to thienopyridine. Patient demographics and clinical characteristics are summarized in Table I. Procedural and vessel characteristics are summarized in Table II.

Table I. Patient Demographics and Clinical Characteristics

Variable
Number of Patients 30
Age (years) 73.8 (40.8-89.4)
Gender (male) 22 (73.3%)
Prior history of CABG 2 (6.6%)
Hypertension 19 (63.3%)
Hypercholesterolemia 8 (26.6%)
Active smoker 8 (26.6%)
Non-insulin-dependent diabetic mellitus 7 (23.3%)
Insulin-dependent diabetic mellitus 4 (13.3%)

Table II. Procedural and Vessel Characteristics

Total number of sirolimus-eluting stents 106
Sirolimus-eluting stents per patient (range) 3.5 (1-13)
Total number of arteries treated with sirolimus-eluting stents 62
   Popliteal artery 7
   Tibio-peroneal trunk artery 23
   Anterior tibial artery 14
   Peroneal artery 9
   Posterior tibial artery 9
Procedural success (%) 100
Stent per patient 3.5
   Mean diameter (mm) 3.1
   Mean stent length (mm) 27.6
Direct stenting (n) (%) 20 (66.6%)
Post-stenting dilatation 1 (3.3%)

There were no restrictions in terms of the number of SES implanted, the diameter of the vessel or lesion length.

Clinical Endpoints

The primary endpoints of the study were overall survival, limb salvage, and primary patency. Clinical major adverse events (MAEs) were defined as death, myocardial infarction, major unplanned amputation, need for surgical revascularization, or major bleeding. Clinical success was defined as continued relief of ischemic rest pain, reduction in severity of claudication, healing of ulceration, and freedom from unplanned surgical amputation or bypass surgery. The need for amputation was dictated by absence of healing or deterioration of ulcer with necrosis.

Because of the severity of disease, including the presence of extensive calcification, it was not possible to measure meaningful and, more importantly, reproducible, ankle brachial indices. Therefore, the patients were followed with clinical examination during their stay in hospital and at 1, 6, and 12 months (then every year) after treatment by percutaneous transluminal angioplasty. Target lesion revascularization was defined as a symptomatic lesion with >50% restenosis. Duplex ultrasound and angiography were performed on those patients representing with symptoms.

The Sirolimus-Eluting Stent

The balloon-expandable sirolimus-eluting coronary stent (CYPHER, Cordis, a Johnson & Johnson company) contains a fixed amount of sirolimus (rapamycin) per unit of metal surface area (148 g of sirolimus per square centimeter). The stent was designed to release 80% of the drug within 30 days after implantation.

Interventional Technique

Sixty-two arteries in 30 patients were treated with a total of 106 SES, an average of 3.5 stents per patient. In addition, 8 patients underwent a supra-popliteal intervention. There was no limit on the number of stents used. If necessary, operators were permitted to use bare metal stents to treat supra-popliteal lesions. The femoral antegrade approach was used in all patients. Interventions were performed through a 5F or 6F sheath. On those occasions when the operator considered the need for better support, then a coronary guiding catheter type JR was deployed. Direct stenting and post-stent dilation were left to the discretion of the operator. Stents were used and deployed with a 100% procedural success. Technical success was defined as success of planned SES implantation, residual stenosis <30%, and recovery of a patent run-off for one trunk at least. All sheaths were removed immediately and vascular access closure devices (ANGIOSEAL, St. Jude) were used systematically to avoid a prolonged manual compression and a reduced distal flow.

Antiplatelet Therapy

Before angiography, all the patients were started on Clopidogrel (75 or 150 mg) daily. For the procedure, after arterial access, patients received intravenous unfractionated heparin (30 UI/kg). Patients were discharged on Clopidogrel (75 mg) for 2 months or longer.

Results

Immediate Outcome

Procedural success, defined as the ability to successfully cross the lesion and implant the stent, was achieved in all patients. Direct stenting was performed in 66% of patients (see Discussion). Post-stent dilation was performed in 3% of patients. The patients were followed with clinical examination during their stay in hospital and at 1, 6, and 12 months (then every year) after treatment by percutaneous transluminal angioplasty. In addition, duplex ultrasound was performed to measure patency of treated vessels. In all cases, the lesions were Type C (occlusive or long tandem-like lesions, never focal and very calcified).

Clinical Outcome

Continued clinical improvement was achieved in 100% of the surviving patients at the mid term follow-up (7.7 months ± 5.8 months). Ninety-six percent of patients achieved Rutherford Category 2 or less at follow-up (Table III). The reduction in severity of claudication was measured by clinical examination and patient feedback. There were no deaths associated with lesions treated with the SES and 100% limb salvage. In two patients with CLI, it was necessary to amputate 1 toe in one and the foot in mid-part in another but without the loss of the limb. Clinical primary patency rate, measured by target lesion revascularization, was 97%. Patency was confirmed by persistent clinical improvement or absence of restenosis >50% by duplex ultrasound or angiography. At mid-term follow up, there were two deaths related to refractory cardiac failure, two patients presented with Grade II ischemic iliac artery stenosis, which was successfully treated by balloon angioplasty or stenting; and one patient with severe ischemic Grade III, due to closure device complication (sub-occlusion by a collagen plug), was successfully treated by endarteriectomy. One patient presented with reperfusion syndrome, which required an extended stay in hospital and hyperbaric care. The patient made a good recovery. One patient suffered a stroke at 6 months after which he continued to have a slight hemiparesia. The number of patients enrolled into the study limits statistical analysis. Never the less, Kaplan Meier analysis results in an overall event-free survival of 92.5% (Fig. 1). The change in Rutherford Classification over time as measured at follow-up of post procedure, 1-month, and mid-term (7.7 months) is shown in Figure 2. Photographic and angiographic examples of CLI treated with SES are shown in Figure 3.

Figure 1. Siro-BTK event-free survival depicted by Kaplan Meier chart.

Figure 2. The graph depicts the change in Rutherford classification over time as measured at follow-up of post procedure, 1-month and mid-term (7.7 months). The red curve depicts the mean clinical evolution. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Figure 3. In a 79-year-old man with symptomatic critical limb ischemia (Rutherford Category 5) due to occlusion of the popliteal artery and a poor collateral flow on the peroneal artery, (A) angiography demonstrates the poor collateral flow in the popliteal artery and its branches. (B) Post-intervention angiography depicts restoration of patency after the deployment of a bare stent on the popliteal artery and 3 sirolimus-eluting stents on the trunk and peroneal artery, resulting in good arterial axis and foot revascularization. At 6-month follow-up, the patient had made a total recovery (Rutherford Category 0), complete wound healing, and full patency measured by Doppler ultrasound.

Table III. SIRO-BTK: Rutherford Category - Pre- and Posttreatment

Pretreatmenta Follow-up at 7.7 months (n = 28)ab
Rutherford Category 0 19 (67.8)
Rutherford Category 1 2 (7.1)
Rutherford Category 2 6 (21.4)
Rutherford Category 3 4 (13.3)
Rutherford Category 4 16 (53.3)
Rutherford Category 5 7 (23.4) 1 (3.7)c
Rutherford Category 6 3 (10)

a Two patients died.
b Values in parentheses indicate percentage values.
c A new lesion above the knee, successfully treated.

Discussion

The most important aim of treatment in CLI is to revascularize the ischemic limb by re-establishing straight-line blood flow to the foot through at least one patent infrapopliteal artery. Interventional techniques have been shown to be a very promising approach; however, in a considerable number of patients, dissections or recoil of the vessel wall after PTA may lead to a suboptimal result with a relatively high risk of sub-acute reocclusion. Like in other areas of the arterial circulation stent, implantation into infrapopliteal arteries has been shown to be an effective technique to optimize the interventional result.

However, while stenting of infrapopliteal lesions is generally accepted as the treatment of choice following a sub-optimal PTA result or a dissection following angioplasty, we wanted to avoid the risk of long dissection after predilatation or multiple balloon inflations [[12]]. Moreover, the long-term patency associated with angioplasty is low [[13]]. Therefore, direct stenting - a proven technique in the treatment of coronary artery disease - was the preferred implantation technique. The only exceptions to this approach were the presence of a total occlusion or the inability to cross the lesion directly.

Another noteworthy point relates to the use of multiple SES. This is not uncommon in treating coronary artery disease. However, in our hospital, and in accordance with the official guidelines on the reimbursement of medical devices, the use of multiple drug-eluting stents is not recommended nor reimbursed. The protocol of this study funded by a grant from Cordis Corporation, restricted device usage to the SES, with no limit in number of stents - the goal being to revascularize the below-the-knee lesion with the same type of stent. In total, 106 SESs were used to treat 62 lesions in 30 patients at an average of 3.5 stents per patient.

Stenting of infrapopliteal arteries for treatment of CLI has the potential to improve both the acute procedural success as well as the long-term clinical outcome. Nevertheless, although 1-year clinical data are very promising, the primary patency rates are in the region of 66% [[14]]. Although this finding may not automatically translate into a recurrence of CLI, deterioration of clinical improvement, prolonged or stagnating wound healing is frequently explained by the presence of early (<4-6 weeks) reobstructions. Particularly, in diabetic patients, the long-term results may be less favorable. From that perspective, the clinical evaluation of drug-eluting stents for the indication of CLI seems to be very important. In our patients with nonhealing ulceration and gangrene, the use of SES is responsible for a prolonged patency (>6 weeks); allows wound healing and limited amputation. Furthermore, given more favorable mid-term results after implantation of this technology, this technique could also be considered for treatment of patients with claudication primarily due to infrapopliteal disease. Our findings are of particular interest as they compare very favorably with two previous studies evaluating SES in the treatment of below-the-knee CLI. In the first, investigators reported a zero rate for amputation [[15]], as compared with 4.3% in the second study [[16]]. Furthermore, the need for target vessel revascularization across the two published studies and our own was only 4%. Likewise, the fate of patients who underwent treatment with SES for their below-the-knee CLI in our study, and the two published studies, can be compared to the known natural history of patients with below-the-knee CLI. Patients undergoing successful intervention with SES had a 100% freedom from major amputation, in contrast to the estimation that over half of patients with CLI will need a major amputation 1 year after developing CLI [[17]]. These outcomes also compare favorably with the 96% limb salvage rates in patients with initial technical success treated by primary stent-supported angioplasty for the treatment of below-the-knee CLI [[18]].

Moreover, while an increasing number of endovascular specialists utilize stents for below-the-knee CLI, some consider the need for studies designed to compare and contrast the use of drug-eluting stents with current therapies such as balloon angioplasty and surgery. To date, only the laser-assisted PTA [[19]] has reported limb salvage rates equal to the reference values observed for a best-case treatment strategy given to patients considered to be suitable for surgical intervention. In our study, the surgeons classified all of the patients as being unsuitable for surgical revascularization. And yet we achieved 100% limb salvage at mid-term follow-up.

Study Limitations

This prospective study involved a small number of patients (n = 30). One year stent patency rate and ankle brachial indexes are not available for all the patients, because it is difficult to impose systematic angiography in this fragile population and ABI, in the majority of the patients, is not applicable due to major arterial wall calcification. However, this on-going registry closely mirrored real world practice with all patients diagnosed with severe ischemia prior to enrolment. The results from our study are very encouraging and worthy of further investigation by randomized, controlled trials. Moreover, the drug-eluting stent must become available in a wider variety of lengths to use it routinely for treatment of infrapopliteal artery disease with relative cost effectiveness.

Conclusion

In this limited patient population, the use of SES for the treatment of infrapopliteal artery disease is feasible and appears to be safe. The SES was not associated with any MAEs and, since it allows sustained and prolonged patency of the distal run-off, which in turn results in wound healing, it appears to hold promise as an alternative therapy for patients with CLI. Finally, we have to compare the cost of using drug-eluting stent technology for this indication against the global cost of a major limb amputation.

Conceptos mas importantes extraidos de la discusion del tema por los autores

Por: Dr. Carlos Alvarez Iorio

El stenting infrapatelar para el tratamiento de la Isquemia Critica Crónica tiene el potencial de mejorar el pronostico agudo del procedimiento así como también el pronostico a largo plazo.Sin embargo aunque los datos clínicos al 1 año son alentadores las tasa de PERMEABILIDAD PRIMARIA se aproxima al 66 %.Aunque este dato no obligadamente se traslada a la reincidencia de la isquemia critica, el deterioro de la mejoría lograda o el retardo o estancamiento de la misma, es habitualmente explicada por la presencia de REOBSTRUCCIONES tempranas (<4-6 semanas)., mas aun en los Diabeticos.Desde esta perspectiva la implantación de Stents con drogas(SES) seria muy prometedora..
En la población de pacientes de este estudio el uso de SES fue responsable de una permeabilidad mas prolongada (> 6 semanas), permitiendo una cicatrización adecuada de la herida y una reseccion limitada.
Estos resultados más favorables se comparan con los obtenidos en 2 trabajos previos con SES para el tratamiento de la Isquemia Crítica provocada por arteriopatia infrapatelar.En el primer trabajo hubo 0% de amputación (1) y en el segundo 4,3%,(2) con una tasa de revascularizacion del vaso culpable en ambos trabajos y el nuestro de 4%.
Si comparamos los resultados de esos trabajos y el aquí analizado observamos que con SES hubo 100% de evolución SIN amputación contra una estimación(historia natural) de un 50% de pacientes portadores de Isquemia Critica.que necesitaran una amputación mayor en el plazo de 1 año..
Las LIMITACIONES de este estudio son que involucro un pequeño número de pacientes y que no específico la tasa de permeabilidad a 1 año ni el índice Braquio-Tibial.
Sin embargo consideramos su importancia quizás radica fundamentalmente en que es un ESTUDIO DE LA VIDA REAL, siendo sus resultados muy notables y estimulantes.

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Autor: Philippe Commeau, MD, FSCAI *, Paul Barragan, MD, Pierre O. Roquebert, MD
Département de Cardiologie et Radiologie Vasculaire Interventionelles, Polyclinique Les Fleurs, 83190 Ollioules, France

Fuente: Catheterization and Cardiovascular Interventions. Volume 68, Issue 5, 2006. Pages: 793-798

Ultima actualizacion: 23 DE NOVIEMBRE DE 2006

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