While a large number of physicians are now convinced that drug elution represents a step forward from angioplasty and bare metal stenting in the superficial femoral artery, there remains a need for clarity and definition about which types of patients and lesions are best treated by which procedures, in what order, what the right combination of drugs and devices is, and what the right time to intervene is.
A satellite symposium at the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) annual meeting, held in Barcelona, Spain (14–18 September), updated delegates on the latest completed and ongoing clinical studies in which the performance of the Zilver PTX paclitaxel-eluting stent (Cook Medical) is being assessed. These studies have been designed to shed light on some of these key questions that physicians face when treating the superficial femoral artery.
Strong Zilver PTX data support longer-lasting treatment for the superficial femoral artery
Michael Dake, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, USA, and one of the principal investigators of the trial, presented the target lesion revascularisation data from ZILVER PTX at CIRSE. These results demonstrated that 83.2% of patients with femoropopliteal lesions who were treated with Zilver PTX did not require revascularisation after four years. In comparison, 69.4% of patients treated with acutely successful percutaneous transluminal angioplasty or provisional bare metal stent placement did not require revascularisation.
Dake remarked, “The four-year freedom from target lesion revascularisation data documents the sustained clinical benefit of Zilver PTX. When compared to standard of care therapy, consisting of either acutely successful angioplasty or provisional bare stent placement after suboptimal angioplasty, the paclitaxel-eluting Zilver stent provides a 45% reduction in the re-intervention rate in this study.”
Dake said that in lesions greater than 10cm, the results showed that the Zilver PTX was “superior to standard of care”, with 82.4% of patients free from target lesion revascularisation using the Zilver PTX vs. 44.9% of patients using standard of care.
Speaking to Interventional News, Dake explained that one specific device or therapy will not sweep the board and be used in every superficial femoral artery lesion. He emphasised that physicians should take a lesion-driven and patient-driven approach when treating the superficial femoral artery.
Four-year data from the ZILVER PTX randomised controlled trial of paclitaxel-eluting stents for femoropopliteal disease, presented at the 2013 Vascular Interventional Advances (VIVA, 8–11 October, Las Vegas, USA) meeting, demonstrate 75% primary patency in the superficial femoral artery at four years for patients treated with the Zilver PTX stent. This compares to 57.9% patency for patients with provisional bare metal stent placement in the study and represents a 41% reduction in four-year restenosis with the paclitaxel coating in the head-to-head comparison of provisional paclitaxel-eluting stent placement vs. bare metal stent placement.
Gary Ansel, director for the Center for Critical Limb Care at Riverside Methodist Hospital in Columbus, Ohio and a co-principal investigator of the ZILVER PTX trial, presented the data.
Multicentre registry confirms positive results of Zilver PTX in an Italian population
Maurizio Grosso, Diagnostic and Interventional Radiology, S Croce Hospital, Cuneo, Italy, presenting the six-month follow-up data from the SMILES (Study multicentric Italian leg eluting stent) registry, told delegates that at the six-month time point, primary patency with the paclitaxel-eluting stent was 90%. The results of this study closely mirrored the data from the Zilver PTX single-arm study, published in the Journal of Cardiovascular Therapy in 2011, where the 12-month primary patency of the stent was shown to be 86.2%.
Grosso said: “Preliminary results of SMILES show that Zilver PTX provides safe and effective treatment in de novo or restenotic lesions in the femoropopliteal artery, above the knee. Zilver PTX also improves quality of life indicators such as walking, leg pain and daily activity. The study confirms the positive results of previous studies, now in an Italian population.”
SMILES is a multicentre, Italian study promoted by the Italian Society of Interventional Radiology, which was designed to collect information about the performance of Zilver PTX in the femoropopliteal segment. The final follow-up is scheduled for 24 months.
“From May 2012 to January 2013, 129 patients were enrolled at 13 hospitals in 11 cities. Among other characteristics, over 9% were type I diabetics and 46.51% were type II diabetics. The mean lesion length of the included patients was 105.50±65.54mm. Grosso stated in his conclusion that at six months, data were available for 88 patients. “The integrity of Zilver PTX was 98.4%; there was improvement in walking in 80.6% of patients, leg pain improvement in 73.8% and improvement in daily activities in 76.1%,” he noted.
Superficial femoral artery treatment approaches reflect a “divided Europe”
Torben V Schroeder, professor of Vascular Surgery, Rigshospitalet and University of Copenhagen, Denmark, spoke about the PESETA (Paclitaxel-eluting stent plus exercise and best medical therapy vs. exercise and best medical therapy for thigh atherosclerosis) trial. He described the design of the study and how improving patients’ fitness with an exercise programme had affected recruitment.
Schroeder told the audience that there are different options for treating infrainguinal occlusive disease, including surgery, angioplasty/stenting and best medical therapy, or a combination of these.
Schroeder told delegates that the one-, two- and now the four-year results with Zilver PTX made his team question whether the “relatively cautious attitude in the Scandinavian countries was reasonable”. He said, “If it is true that the drug-eluting stent is significantly better, with long-lasting results that are superior to best medical therapy or plain angioplasty, then more patients should be considered for stenting.”
In order to find out if a shift in the way claudicant patients are treated in Scandinavian countries was needed, Schroeder and colleagues started a randomised controlled trial to assess whether there was a durable, beneficial effect Zilver PTX in patients with stable claudication who have a femoropopliteal lesion and are suitable for endovascular management. To be included in the study, patients had to exercise for three months and be on best medical treatment.
“Unfortunately, the three-month run-in period in our trial, including best medical therapy, structured exercised training using a logbook, regular outpatient visits and counselling, was so successful that 80% of the patients were not interested in interventional treatment. This raised the question, should other factors be considered more carefully than the haemodynamic and exercise effects?” Schroeder questioned.
He concluded that, given the fact that Zilver PTX may provide a substantial improvement in peripheral arterial disease patients, “this could justify a paradigm shift; however, the concept needs to be confirmed in a randomised controlled trial”.
In the ensuing discussion, Marc Bosiers, Belgium, made the point that other than Scandinavia and the UK, there was a “different Europe” where claudicants wanted “swift treatment”. “These patients are not willing to undertake walking exercises, and will go into other hospitals to get intervention. The patients we treat for claudication are well-treated, and very happy with their sustained results. If they come back with a problem, we have the endovascular tools to help them again,” Bosiers said.
Zilverpass study to compare Zilver PTX with surgical bypass in long lesions
Bosiers told delegates that the Zilverpass randomised trial would compare the performance of the Zilver PTX stent to the results of classical above-the-knee bypass for Transatlantic Intersociety Consensus (TASC) II C and D lesions. Twelve-month results from the subgroup analysis of the ZILVER PTX trial single-arm study of TASC II C and D de novo lesions have indicated that endovascular therapy outcomes with Zilver PTX may equal those of bypass surgery.
Investigators in the Zilverpass study will randomise 220 patients so that half of them get a classical above-the-knee bypass, and the other half will receive a Zilver PTX stent. Primary patency will be defined equally in both arms as the absence of binary restenosis using a dedicated corelab duplex at one, 12 and 24 months. The study will take place in four countries: Belgium; Germany; Italy and Brazil.
Bosiers, Department of Vascular Surgery, AZ St-Blasius, Dendermonde, Belgium, said: “If you compare an endovascular intervention with an open one, your definition [of the endpoint] needs to be the same. In surgical publications, a bypass is open until it is closed, so an open surgery bypass cannot, theoretically, have a 90% stenosis; if there is flow, it is open in the vascular world. In the endovascular world, we are used to the term “absence of binary restenosis”, so if you put a stent in an artery and after one year you have a 60% stenosis, primary patency is considered as lost.
“In our service we looked at 100 surgical open bypass cases and looked at the proximal and distal anastomoses. We were eager to see if there was a binary restenosis at the proximal or distal anastomoses in the vascular world. We saw that in 11 cases, although they would be classified as open in the vascular world, in the endovascular world, they would have been classified as having lost their primary patency. So if you translate this to a 78–80% primary patency, you then have similar results with an open bypass as with endovascular treatment.”
While providing an overview of the literature, Bosiers noted that “We know nowadays that if you look at TASC A and B lesions, an overview of the randomised trials shows that stents perform better than balloons. So, in Europe at least, there is an approach to use nitinol stents (drug-covered, or not) to treat these types of lesions. The question is what happens in long lesions.”
Bosiers referred to the three publications from randomised controlled trials that could shed some light. The DURABILITY II trial focused on long lesions to specifically test the performance of a single 200mm stent (Everflex, Covidien) in the superficial femoral artery. The trial looked at the durability of the EverFlex stent in lesions that were up to 24cm in length. The primary patency at one year was 64%. Therefore, Bosiers said, “a full metal jacket (as full lesion stenting is sometimes referred to) is an option that gives you this result. In the VIASTAR randomised controlled trial study, 12-month results in patients with 19cm lesions, achieved a 78% primary patency for the Viabahn stent graft (WL Gore) vs. nitinol stents. In the Zilver PTX registry, 12-month primary patency, where the mean lesion length was 23cm was 77.6%. Two-year freedom from target lesion revascularisation was around 80%.
“If you look at these trials, it seems like the Viabahn scores a little bit lower than Zilver PTX when you look at the lesion length and the Zilver PTX is a little bit better than the bare nitinol stent if you look at the primary patency. I am a vascular surgeon who performs surgical bypass and for the moment, the best in class in the endovascular world seems to be the Zilver PTX for long lesions. So we are eager to compare the effects of Zilver PTX against surgical bypass above the knee (which shows an approximately 78–80% primary patency using synthetic grafts such as PTFE or Dacron) in a randomised fashion,” he said.
REAL PTX: Drug-eluting stent vs. drug-eluting balloon
The REAL PTX trial is designed to carry out a head-to-head comparison of Zilver PTX with a paclitaxel-eluting balloon.
Dierk Scheinert, Center for Vascular Medicine, Park Hospital Leipzig, Leipzig, Germany, and the principal investigator of the REAL PTX trial reported on the background and setting up of the study. He said that the trial is an investigator-initiated, prospective, randomised, European, multicentre, pilot study designed to directly compare the drug-eluting stent, Zilver PTX, with a paclitaxel-eluting balloon in the treatment of symptomatic peripheral arterial disease of the femoropopliteal artery.
Scheinert briefly reviewed the literature to state that drug-eluting balloons have been shown to have a significantly lower restenosis rate than plain balloons. This has, Scheinert noted, been determined by five randomised, controlled trials, and was a relatively strong proof of concept. He also stated that Zilver PTX had been shown to have a significantly lower restenosis rates than bare metal (Zilver) stents as confirmed by randomised, controlled trial data. “Zilver PTX is the only device on the market in that category to show this benefit,” he stated.
“Twelve-month restenosis rates for drug-eluting balloon trials and Zilver PTX trials show that there are more data points for drug-eluting balloons than drug-eluting stents for relatively short lesions. There is not much published literature on drug-eluting balloons to show how drug-eluting stents and drug-eluting balloons compare for longer lesions,” Scheinert noted.
Scheinert posed the question: are stents needed after the use of drug-eluting balloons in the superficial femoral artery? “How should we implement stents into the treatment strategy? In the balloon trials, there was clearly an attempt made to use stents as minimally as possible because [the use of stents] would impact the ‘value proposition’ for drug-eluting balloons, which is to provide a solution without leaving metal behind,” he said.
Scheinert also made the point that drug-eluting balloons have so far been tested in “rather benign lesions.” The stenting rate in the THUNDER trial was 4% vs. 22% for the control group. In the FemPac trial, the stenting rate was 9% in the drug-eluting balloon group and 14% in the control group. Therefore, stenting rates are artificially low as we did not want to implement bailout stenting,” he said.
Showing some cases, Scheinert told delegates that calcified arteries were a limitation for balloon technology as recoil and residual stenosis were observed after treatment. “Highly calcified lesions primarily require a mechanical treatment,” Scheinert reported.
The REAL PTX trial will provide insights for subgroups with different lesion lengths, stated Scheinert. Enrolled patients (n=150) will be stratified according to lesion length into three groups: patients with the lesion length ≤10cm; patients with the lesion length >10cm and ≤20cm, and; patients with the lesion length >20cm and ≤30cm. Fifty patients will be assigned to each group.
Scheinert reported that 91 out of a planned 150 patient had been enrolled and that the end of enrolment had been planned the final quarter of 2013. This will enable us to “realistically present the first results in LINC 2015,” he noted.
Real-world experience with Zilver PTX
Peter A Gaines, Sheffield Vascular Institute, Northern General Hospital, Sheffield, UK, spoke to delegates about his experience with Zilver PTX in the treatment of intermittent claudication.
Gaines first established the importance of patency by referring to a study by Karsh et al, published in the Journal of Vascular Surgery in 2000, and saying: “At five years, clinical success absolutely matches the anatomical patency of the conduit, so if the claudication returns, you can be sure that the conduit has gone down. So, patency is one of the most important factors that affect the clinical success of treating claudication.”
Regarding critical limb ischaemia, Gaines used a study of diabetic patients, published by Dick et al, to demonstrate that patency could improve through re-intervention after angioplasty and that clinical success increases from 22% up to 46%. “Therefore patency is important in treating critical limb ischaemia,” he said.
Gaines then made the case for intervening in claudicants by showing that the quality of life of patients with claudication, as measured by the SF-36 questionnaire (Short Form 36; a patient-reported survey of patient health), improved substantially in every domain after intervention. He also reported that patients were so keen to have treatment that they were willing to “run a 13% risk of death from the procedure and lose between two to eight years of life” in order to undergo interventional treatment for claudication. These findings were obtained from survey whose results were published by Letterstall et al in the Journal of Vascular Surgery in 2008. Gaines maintained that the quality of life for many claudicants was similar to that of dialysis patients and that it could improve significantly by treating their claudication with endovascular treatment. “Patency affects the outcomes of treating claudication patients and patients with critical limb ischaemia. There is a responsibility to maximise patency,” Gaines told delegates.
Answering the question “does Zilver PTX improve the outcomes of superficial femoral artery intervention?” Gaines said: “Why do I use the Zilver PTX? Because four-year freedom from target lesion revascularisation is significantly better in the paclitaxel group and so is the three-year primary patency, such that you have a 45% reduction in restenosis rate due to the drug,” he said.
Gaines outlined how he would use the Zilver PTX stent in his practice for intervention in both claudication and critical limb ischaemia. “For short stenosis, I would carry out a percutaneous transluminal angioplasty; for occlusions that are short of full length in claudicants and for long and diffuse stenoses, I would use a Zilver PTX stent; for a full length superficial femoral artery occlusion, I would recommend a bypass, or subintimal angioplasty, if the patient is unsuitable for bypass,” he said.