First Clinical Application of Absorbable Metal Stents in the Treatment of Critical Limb Ischemia: 12-Month Results

Introduction

Peripheral stents aim to support revascularization procedures of intravascular stenoses by mechanically preventing vessel recoil and counteracting pathophysiologic processes of luminal re-narrowing triggered by procedural injury of the vessel wall. Despite improvements in stenting techniques and concomitant medication, repeated intervention due to target lesion restenosis is necessary on a significant percentage of patients. The permanent presence of an artificial implant plays a prominent role in the discussion of mechanisms causing in-stent restenosis. Permanent metallic implants pose the risk of a continuous interaction between non-absorbable stent and surrounding tissue, leading to physical irritation, long-term endothelial dysfunction, or chronic inflammatory reactions.¹ In addition, there is a risk of stent fracture due to external mechanical forces. To overcome these shortcomings, the technology of stenting has moved towards the development of temporary implants composed of biocompatible materials that mechanically support the vessel during the high-risk period for recoil and then completely degrade in the long-term perspective.^2-6 This removes a potential trigger for late restenosis.⁷ The intended performance of an AMS is to mechanically prevent early vascular recoil (short-term effect), to lose mechanical stiffness after acute risk of recoil is eliminated and thereby enable positive remodelling of the vessel wall (mid-term effect), to be absorbed completely (long-term effect) and, at any point in time, to minimize pathophysiologic mechanisms of restenosis through its material properties. During the development of the AMS, several technical requirements were fulfilled. Mechanical properties should be very similar to those of stainless steel and maintain its mechanical integrity for the initial period of time after implantation. In order to avoid inflammatory and foreign body reactions, the metallic material should mainly consist of elements present in the human body. Moreover, the unwanted side-effects, such as toxicity and thrombogenicity, should be avoided. Magnesium was found to be an ideal basis for developing an absorbable metal stent meeting all technological and clinical requirements.⁷ A specific magnesium alloy containing magnesium (more than 90%) and other rare earth elements was selected for stent construction. The tubular-slotted, balloon-expandable stent is sculpted by laser from a single tube of a bioabsorbable magnesium alloy. The stent, sized 3.0 mm in diameter and 10 or 15 mm in length, is pre-mounted on a 6F rapid-exchange delivery system with 0.014" inner distal lumen. Animal investigations demonstrated superior in vivo performance of the AMS,7 in particular, higher in-stent minimal lumen diameter (MLD) compared to conventional metal stents, paving the way to their clinical application. After having documented 3-month results of this first worldwide clinical application of the recently developed Absorbable Metal Stent (Magic, BIOTRONIK, Germany) in 20 CLI patients,¹³ we present final clinical results of the patients treated with AMS after 12 months in this communication.

Methods

Between December 2003 and January 2004, 20 patients were treated with AMS in 2 clinical centers. Nine patients have been classified as Rutherford class 4 (ischemic rest pain) and 11 as class 5 (minor tissue loss). Patients had a mean age of 76 ± 8 years (range 59-96); 10 were male and 10 were female. Risk factors included previous peripheral vascular intervention (16 patients), hypertension (14), coronary disease (11), obesity (10), diabetes (10), nicotine abuse (10), hypercholesterolemia (8), renal insufficiency (4) and cerebrovascular disease (3). Patients had diagnosed atherosclerotic lesions of 84% (70-95%) stenosis in the proximal two thirds of one or more of the infrapopliteal arteries. Lesion length was 11 mm (2-20 mm), i.e. the lesions could be covered with one or two stents of 15 mm in length. Target vessel diameter was 3.0 mm. Written patient consent was required prior to patient enrollment. Local ethics committee approval was received prior to study initiation. This study was conducted in accordance with the Declaration of Helsinki. During the procedure, inflow-limiting stenoses of vessels above the knee was treated before the lesion below the knee was addressed. After successful passage of the lesion below the knee using a guide wire, diagnostic angiography of the lesion area and distal run-off were performed. The lesion was then dilated with a coronary Percutaneous Transluminal Angioplasty (PTA) balloon under angiographic control. In case of insufficient restoration of blood flow by PTA alone, the stenosed area was treated by maximally 2 AMS implants. Immediate procedural success, defined as less than 30% residual stenosis, as well as post-procedural vessel run-off were confirmed by angiography. To assess good stent positioning of the radiolucent stents, IVUS control (Volcano Therapeutics Inc., Rancho Cordova, CA) was performed at the end. The aim of treatment was to restore one straight line of flow to the foot. Antiplatelet therapy was administered for at least one month after the procedure. All patients were closely monitored during the first year after implantation (day 1, 30, 90, 180, 270, 360). At the different control visits, post-procedure blood sample analysis (haematology, electrolytes, inflammatory parameters fibrinogen and C-reactive protein (CRP), liver, bile, pancreas, kidney/excretion) was been performed to prove the biocompatibility of the stent material. The occurrence of in-stented area restenosis has been investigated by color flow duplex ultrasound (CFDU) at every follow-up visit, with significant restenosis being defined as doubling of the proximal peak velocity rate. Mortality and limb salvage, defined as freedom from major amputation, have been recorded at the different follow-up visits. Survival, primary patency, secondary patency and limb salvage rates were calculated according to the Kaplan Meier method.

Results

Procedural Results

In 14 patients, lesions were calcified. Thrombus was diagnosed in 3 patients and ulceration was diagnosed in one patient. A total of 23 AMS were implanted in 20 infrapopliteal lesions, the mean length of treated lesions was 11 mm (2-20), with an average reference vessel diameter of 2.7 mm (2.5-3.0) and a stenosis grade of 84% (75-95). Lesions were located in the proximal third of the anterior tibial artery (in 6 patients), mid third anterior tibial artery (1), tibio-fibular trunk (5), proximal third fibular artery (7) and proximal third posterior tibial artery (1). The average procedure time was 56 ± 31 min (range 20-130). All stents were implanted at a delivery pressure of 16 atmospheres. Postdilation of implanted stents to maximally 3.2 mm was performed in 5 cases to further improve stent apposition following IVUS analysis. Angiographic procedural success, defined as 30% or less residual stenosis on visual assessment of the planned area of treatment after completion of treatment without serious adverse events and before the arterial sheath is removed, was achieved in all 20 patients. Post-procedural IVUS control (performed in 19 patients) confirmed a good stent positioning, and a homogenous and complete inflation of the AMS device in all investigated patients, as well as a low immediate elastic recoil comparable to conventional metal stents. The average improvement in Rutherford class due to procedure was 1.8 (range 1-4). Median surveillance was 373 days (range 24-407). One patient died 24 days after the procedure due to pneumonia following the intervention. One patient presented at day 43 with occlusion of the femoro-peroneal bypass, stopping inflow to the stented region as well. A venous bypass was implanted at day 97 and due to continued deterioration, amputation of the limb was necessary at day 125. Finally, due to a pneumonia developed after the amputation, the patient died at day 137. During the bypass procedure, the stented area was removed and made available for histologic analysis. CFDU revealed significant restenosis in 3 patients after, respectively, 85, 107 and 181 days. Since none of the patients suffered clinical deterioration, it has been decided to continue with further conservative treatment. A third patient died at day 225 due to natural causes. One patient presented with reoccurrence of rest pain at day 337; angiography revealed occlusion of the treated segment. Laser-assisted angioplasty (CVX-300 excimer laser, Spectranetics, Colorado Springs, CO) was performed to reopen the vessel. The Kaplan Meier graphs for mortality, primary patency, secondary patency and limb salvage showed 12-month rates of 85.0%, 73.3%, 78.9% and 94.7%, respectively. Regular CFDU measurements clearly demonstrated a continuous absorption process indicated by decreasing intensities of stent struts over time and a complete invisibility of stent material at 12 months. Analysis of blood sample parameters did not yield any significant changes at discharge with respect to any investigated parameter. Blood analysis at follow-up visits showed values in the normal range. The tissue explanted during surgical removal of the occluded region in the one patient at day 97 was analyzed in detail. The tissue was embedded in methacrylate and histologically prepared. The staining was performed using HE- and Ca-method. Remains of the stents could be seen as grey patterns in the longitudinal cut vessel. This indicates that the stent was almost completely degraded 10 weeks after the implantation. There was no necrosis detectable, and inflammation was found to be moderate. Histologic analysis shows that the core of the former stent struts still shows some metallic areas, whereas in the outer regions, the original strut material is replaced by a dark material that has a grey-blue color in HE, and red color in the applied Ca-staining. The degradation product mainly consists of Ca and P, as shown by energy dispersive x-ray measurement. This is consistent with theoretical models for the absorption process. Magnesium is transformed to magnesium hydroxide, which is further transformed to soft calcium compounds like calcium phosphate and hydroxyl apatite in the mid-term perspective.

Discussion

The patient population of the first clinical application of AMS serves as a challenging practical test for a completely new device. Poor success rates of percutaneous interventions have been reported in literature for patients with symptomatic CLI of Rutherford class 4 and 5 as well as diagnosed lesions of infrapopliteal arteries.^8-12 Despite the frequent use of stents for various indications of peripheral vessel repair, the angioplasty of below-the-knee lesions with stenting support is far from being the treatment of choice in daily practice, due to the pronounced risk of stent crush combined with a low expected improvement of vessel patency. The presented clinical application was analyzed to prove the general safety and feasibility of the tested device and indicate the clinical performance for this indication. An excellent procedural success rate demonstrates that handling and procedural effectiveness are not different from established stainless steel stents. The absence of any changes in blood parameters did not give evidence for remarkable inflammation or toxicity and indicate a good biocompatibility. After 12 months, the resulting values for primary clinical patency and limb salvage indicate a promising performance in the treatment of below-the-knee lesions. Based on the experience of the presented first clinical application of AMS on a magnesium alloy basis, the vision of a degradable stent with adequate clinical performance seems to come closer to reality. Limitations of the presented clinical application are the small number of patients treated with the device, the unavailability of quantitative angiographic follow-up data and the lack of reference data for infrapopliteal stenting. Although the effectiveness of the newly developed AMS based on a magnesium alloy is not yet proven with statistical significance, the presented data clearly indicate that this system has potential to establish a new therapeutic strategy for clinical practice. A recently started multi-center, prospective, randomized trial comparing PTA versus AMS implantation for infrapopliteal lesions will give more insights in the clinical performance of this system in infrapopliteal application.

Acknowledgements

The authors thank Koen De Meester, Erwin Vinck and Matthias Schier for their contribution to the work presented.

Correspondence: marc.bosiers@pandora.be