Stenting statistically superior to balloon angioplasty in the superficial femoral arteries
The outcomes of trials assessing the use of stents for treating peripheral arterial disease (PAD) in the superficial femoral arteries (SFA) and proximal popliteal arteries have so far had mixed results (SIROCCO, FAST, ABSOLUTE). However, the latest results from two trials have demonstrated the superiority of the LifeStent NT (Edwards Lifesciences) compared to balloon angioplasty, and the effectiveness of the Zilver PTX drug-eluting stent (Cook Medical) compared to bare-metal stents.
The RESILIENT Trial
The RESILIENT Trial is a prospective, multi-centre trial of angioplasty alone versus angioplasty plus stenting in patients with peripheral vascular disease in the superficial femoral artery (SFA) and proximal popliteal artery. This is the first randomised trial of percutaneous transluminal angioplasty (PTA) versus stenting using new self-expanding, nitinol mesh stent technology, and it was designed assess the value of SFA intervention with nitinol mesh stents versus PTA alone. The co-Principal Investigators of The RESILIENT Trial are Drs Barry T Katzen, Founder and Medical Director of Baptist Cardiac & Vascular Institute, Miami, FL, and John R Laird, Medical Director of the Vascular Center at the University of California, Davis Medical Center.
The Phase II (Pivotal) study is a randomised, prospective, multi-centre study. The purpose of which is to evaluate safety and efficacy of the Edwards LifeStent compared to PTA alone for the treatment of de novo or restenotic (non-stented) lesion(s) of the native SFA and/or proximal popliteal artery. Patients were randomised to control (PTA-alone) or treatment (PTA with stenting) on a 1:2 basis. A total of 206 patients were enrolled, with 134 patients receiving PTA plus stent and 72 PTA alone (Figure 1). Clinical evaluations are planned at 30 days, six months, 12 months, 18 months, two and three years. Duplex follow-up was planned up to 12 months. Safety endpoints for the study include periprocedural death, stroke, myocardial infarction, emergent surgical revascularisation, significant distal embolisation in the target limb, and thrombosis in the target vessel. Efficacy endpoints for the study include vessel patency and target lesion/vessel revascularisation.
The Edwards LifeStent Peripheral self-expanding nitinol stent system is specifically designed to withstand the levels of dependent stress placed upon a stent in the superficial femoral artery. Due to its unique helical design the LifeStent Peripheral Stent System provides physicians with a unique and highly flexible intraluminal scaffold with sufficient radial strength to address clinical needs in a challenging area of the anatomy. Its highly flexible nature allows the LifeStent stents to be bent up to 180 degrees or even twisted without kinking.
Inclusion criteria included: lifestyle limiting claudication defined as Rutherford category 1-3 (mild to severe claudication); the target lesion(s) must meet the following criteria: de novo or restenotic (stenosed, occluded, restenosed, or re-occluded) located within the native SFA and/or proximal popliteal artery (3cm above the knee joint and 1cm below the origin of the profunda femoris artery); lesion length per lesion not exceeding 150mm; if the lesion(s) is restenosed or reoccluded prior PTA-only treatment must have occurred >6 months prior to the study procedure; the target lesion(s) has angiographic evidence of stenosis or restenosis >50% or occlusion and is amenable to PTA-alone or PTA plus stenting; the target vessel reference diameter is >4.0mm and <7.0mm; there is angiographic evidence of at least one vessel runoff to the foot. Prior to enrolment/ randomisation, access is obtained to the target vessel and the balloon (uninflated) is passed across the most distal target lesion. Randomised allocation to either PTA or PTA plus LifeStent was then obtained. There was no significant difference found in the baseline lesion characteristics for both groups in terms of degree of calcification, length, location or type, following Core Lab analysis. During actual enrollment, 29 (40.2%) patients in the PTA arm could not be sufficiently treated with PTA alone and underwent additional bailout stenting. Although these patients are considered as cross-overs, they remain in the PTA group for the mandatory primary analysis per Intention to Treat (ITT). The major reasons for bailout stenting was flow limiting dissection (grade C or greater) in 11 (38%) and a residual stenosis >30% in 18 (62%) of the bailout cases. All bailouts were confirmed to be acceptable per protocol by the independent angiographic core lab or via site-source documentation in two patients. Bailout stenting is considered a target lesion revascularisation, a primary endpoint and patency failure. The bailout lesion and patient characteristics show that longer and more calcified lesion are mainly present the bailout group. when compared to the PTA alone group. This also resulted in more severely diseased patients, as expressed by the higher proportion Rutherford category three patients in this group. Katzen said, this clearly shows, in a controlled study, what we also know long time from other literature that with a PTA alone strategy the longer, more calcified lesion in the SFA, can unlikely be treated with a PTA alone strategy. Other factors as the presence of an occlusion and or an excentric stenosis contribute also to a failure of a PTA alone strategy, but this evaluation was not part of the study design. The mean stented length in the LifeStent group was 99 +/- 50mm.
30 days and six-month results
There was also no incidence of death, stroke, myocardial infarction (MI), emergent surgical revascularisation, thrombosis or renal failure in either groups of patients up to 30 days. Those acute safety result analysis show a high level of safety for both groups, with no additional risk periprocedure and at 30 days related to LifeStent implantations. At sixmonths, a primary patency (Duplex) of 50.1% in the PTA and of 94.6% in the stenting arm have been recorded. Freedom from re-intervention was 54.1% and 95.3% respectively. Katzen reported five stent fractures within the first six month, equating a fracture rate of 1.2% (data from CIRSE 2007).
On Tuesday 23 October 2007, Dr Katzen presented the 12-month results at the Transcatheter Cardiovascular Therapeutics (TCT) scientific symposium in Washington, DC. He said the results of this trial show the statistical superiority of the LifeStent selfexpanding stent versus PTA alone as the need for follow-up intervention was 13% versus 54%, respectively, at 12 months. The RESILIENT Trial further demonstrated the SFA stent patency (duplex) rate was 80% for patients who received the LifeStent selfexpanding stent versus 38% for patients with PTA alone. At 12-months, 86% of patients from both groups remained free of Major Adverse Clinical Events (MACE) (p=0.91), however the PTA plus stent strategy showed statistically significantly better results in regard to primary patency (p<0.0001), freedom from target lesion revascularisation (p<0.0001) and clinical success (p<0.0001) (Figure 2). In addition, the investigators identified nine stent fractures (2.9%) up to one year but none of these were associated with restenosis. The Type IV fractures (n=5) may be explained by poor deployment technique, as the study was carried out with the first generation LifeStent NT delivery system, but other factors may additionally contribute. To avoid overlapping stents, investigators also recommend a one-stent strategy when viable. At time of the study only LifeStents with the lengths 40, 60 and 80mm were available. Stents with longer lengths are now available. The results of an analysis of the Quality of Life data also revealed that the stent group demonstrated a dramatic improvement over baseline at six months and with sustained improvement/ benefit at 12 months.
In conclusion, Katzen stated that the results from The RESILIENT Trial clearly show with level 1 evidence, that in claudicants, with lesions in the SFA and proximal popliteal artery up to 150mm, a primary stenting strategy with the LifeStent is superior to a PTA alone strategy. This demonstrated periprocedurally by a larger luminal diameter, lesion success and procedure success, and by primary patency and freedom from Target Lesion Revascularisation at one-year. Importantly, PTA plus LifeStent did not lead to a higher rate of major clinical adverse events than PTA alone.
Professor Michael Dake, University of Virginia Health System, Virginia, presented a discussion at the Cook Medical sponsored symposium held at this year’s Cardiovascular and Interventional Radiological Europe (CIRSE) meeting, entitled ‘Zilver PTX Clinical Trial Update’. Dake began by explaining that the Zilver, bare metal stent platform is a self-expanding nitinol stent, has enhanced flexibility and excellent expected durability. In addition, the Zilver PTX drug-eluting stent (DES) has a paclitaxel coating only (no polymer or binder), thin coating (<5μm) and 3μg/mm2 dose density. The indications for Zilver PTX generally include treatment of symptomatic disease of the above-the-knee femoropopliteal artery, and reference vessel diameter of 4–9mm. Also included are ‘Phase 1’ lesions, ie. ≤7cm (one Zilver PTX stent per limb), ‘Phase 2’ lesions, ie. ≤14cm (two Zilver PTX stents per limb), and Global Registry; maximum of four Zilver PTX stents per patient.
Present clinical trial status
Dake, national principal investigator for the Zilver PTX Drug-Eluting Stent Trial discussed the importance of the multi-centre, prospective, randomised trial comparing Zilver PTX to balloon angioplasty (PTA) for femoropopliteal above-the-knee lesions. Enrolment is complete (n=60) for the Phase 1 component of the trial, and enrolment is currently underway for Phase 2 (expected number of patients will be 420). Reporting the six-month results for the study, Dake said that patients were randomised to Zilver PTX or PTA, and at the study initiation, PTA was considered the standard of care. He added that patients experiencing PTA failure will undergo second randomisation to Zilver PTX or bare Zilver. Follow-up is five years. Phase 1 follow- up ranged from six to 12 months, with a average of nine months.
A Global Registry Study is also currently underway, with more than 520 patients already enrolled, and 1,050 stents implanted. The expected number of total enrolled patients is 760. The study will include 50 sites, across Europe, Asia, North America and South America. Dake explained that the Registry is an 1000-patient pool with Zilver PTX to assess the incidence of potential rare adverse events. Follow-up be two years, and in terms of complex lesions, there is no explicit length limitation, and up to four Zilver PTX stents per patient can be administered. Dake reported on the first 70 patients at ten sites with complete sixmonth follow-up. Demographics for both the Phase 1 randomised study and Global Registry can be seen in Table 1. Lesion characteristics for each study can be seen in Table 2. In the PTA arm, there were 33 treated lesions versus 29 in the Zilver PTX (ZPTX) arm. Ninety-two lesions were treated in the Global Registry. According to the TransAtlantic Inter- Society Consensus (TASC) criteria, 39% of lesions in the PTA arm were classified as class A, versus 45% in the ZPTX arm and 13% in the Global Registry. Total occlusion was 15%, 14% and 40% in the PTA group, ZPTX group and Registry, respectively. Baseline angiographic data are shown in Table 3.
Dake reported on Zilver PTX stent integrity at six months. The Phase 1 randomised study demonstrated that in 41 stents there were 0 fractures. In the Registry, from a total 181 Zilver PTX stents, it was reported that there were two potential strut fracture – one possible Type 1 (single strut) and one possible Type II (few individual struts). Investigations into this are ongoing. Therefore, overall there was a 0.9% chance of fracture in the Zilver PTX stent (222 stents with two potential fractures).
Six month outcome
Dake reported that event-free survival defined as freedom from both Major Adverse Events (MAE), (including death, target lesion revascularisation [TLR], target limb ischaemia requiring intervention and surgical repair of the target vessel), and worsening of Rutherford Classification (by two classes or to Class 5 or 6), was 91% in the PTA group, 89% in the ZPTX group and 87% in the Registry (Table 4). The effectiveness data that is available includes primary patency, which ends with acute PTA failure, revascularisation, or >50% DS on imaging (ultrasound or angiography), explained Dake. In terms of revascularisation, reintervention or surgical bypass was performed for >50% angiographic DS within ±5mm of the target lesion, after recurrent clinical symptoms. Freedom from TLR in the randomised study was 52% in the PTA arm and 90% in the ZPTX arm. In the Global Registry, TLR was 90% (Table 5).
In summary, Dake announced that the Zilver PTX DES has an “excellent safety profile” and “excellent device integrity” (0.9% rate of potential fractures at six months). He added that stenting is more acutely effective than PTA(TLAfree: 90% PTX vs. 52% PTA), and following acute PTAfailure, Zilver PTX appears to have better effectiveness than bare-metal Zilver stent.