Clinical Trial Update

Two-Year Results of IMPERIAL: First-Ever Randomized Study of Eluvia and Zilver PTX in Femoropopliteal Artery Lesions

An interview with IMPERIAL trial co-principal investigator William A. Gray, MD, FACC, FSCAI, System Chief, Division of Cardiovascular Disease; President, Lankenau Heart Institute, Main Line Health, Wynnewood, Pennsylvania.

An interview with IMPERIAL trial co-principal investigator William A. Gray, MD, FACC, FSCAI, System Chief, Division of Cardiovascular Disease; President, Lankenau Heart Institute, Main Line Health, Wynnewood, Pennsylvania.

IMPERIAL is a global, randomized, controlled trial (n=465) comparing the Eluvia paclitaxel-eluting nitinol stent (Boston Scientific) with the Zilver PTX paclitaxel-coated stent (Cook Medical) for treatment of femoropopliteal artery lesions. It is the first head-to-head trial comparing two different drug-eluting stent systems for the treatment of peripheral arterial disease. One-year data were reported in 20181 and the 24-month data were recently presented at the October 2019 Vascular InterVentional Advances (VIVA) meeting in Las Vegas, Nevada.

Multiple challenging lesion and disease characteristics were represented in the IMPERIAL trial. For Eluvia and Zilver PTX groups, respectively:

  • Mean lesion lengths were 86.5 ± 36.9 mm and 81.8 ± 37.3 mm;
  • 42% and 44% of patients had diabetes;
  • 31% and 30% of patients had occlusions.

At 24 months, the Kaplan-Meier estimates of primary patency were 83% and 77.1% for patients treated with Eluvia and Zilver PTX, respectively (log-rank P=.10). The clinically driven target lesion revascularization (TLR) rate was significantly lower for patients treated with the Eluvia stent (12.7% vs 20.1%; P=.0495).

The Eluvia stent utilizes a drug-polymer combination that provides a sustained release of paclitaxel over one year. It is built on Boston Scientific’s self-expanding nitinol Innova stent, which has been specifically designed for use in the superficial femoral and proximal popliteal arteries.

How do you make the choice to stent in the femoropopliteal vessels?

The classic evaluation for stenting therapy in any superficial femoral artery (SFA)/popliteal intervention usually relies on the answers to a few key questions. First, how good was your balloon angioplasty result? Did it fully relieve the stenosis? And in the process of doing so, did it leave a bad dissection that might be flow limiting? Other reasons people will stent include calcification and resistant lesions. Some people will come into the procedure knowing they will want to stent, but many will make that decision along the way, depending on how well the procedure progresses.

Can you describe the IMPERIAL trial and share some of its unique aspects?

The IMPERIAL trial was designed several years ago, and is a very unique trial in two different ways. First, the device itself, the Eluvia stent (Boston Scientific), is very unique, because the previous SFA stent iteration from Cook (Zilver) is a paclitaxel device, but does not utilize a polymer to regulate how much and when the paclitaxel is delivered to the SFA/popliteal vessels, resulting in an early higher dose delivery of paclitaxel, but without much in the way of a sustained release. Due to the positive results from the Zilver PTX trial, Boston Scientific thought that they might be able to create a stent with a better profile for drug delivery by adding a polymer to the paclitaxel to allow for the modulation of how much and how long the paclitaxel would be delivered. Eluvia is the first paclitaxel-eluting stent for the femoropopliteal arteries with a long-term elution profile. Paclitaxel releases at a low dose over many months in order to address the restenosis cycle in the SFA/popliteal arteries, which tends to peak somewhere between 10 and 12 months. The second unique component of the trial was that IMPERIAL is the first head-to-head major trial of any paclitaxel therapy in this space. The trial was designed to have Eluvia go up against the predicate Zilver drug-coated stent.

The results of the one-year trial primarily evaluated whether Eluvia was non-inferior to the Zilver stent, and if that criteria was satisfied, then a superiority analysis was invoked. In fact, both analyses ended up being positive. Eluvia was found to be not only non-inferior to Zilver, but also superior to Zilver, in the primary endpoint of primary vessel patency at one year.1

The 2-year data was reported at VIVA in October. What did you conclude from the results, particularly regarding the target lesion revascularization (TLR) rate and mortality?

The most important thing in anything we do is safety. The safety profile of Eluvia at 12 months was excellent, and was actually as good as and trending better than Zilver; at 24 months, the safety was again maintained. TLR was also maintained at a very low rate. Actually, the TLR rates are comparable at two years to what many devices reach at one year. At 2 years, the Eluvia stent has performed exceptionally well into what I would call an intermediate phase of follow-up.

How far out will you be tracking patients?

Per FDA guidance, we will be following patients out to five years for safety, and IMPERIAL will be following efficacy by monitoring TLR out to five years as well.

Is there a difference in the restenosis pattern that might be favorable for one stent over another?

It’s an important question, but those analyses haven’t been done yet, but so we don’t know for certain.

The Eluvia stent differs from the Zilver PTX in that it utilizes a polymer. What else is appealing to you about the Eluvia stent?

Well, at its core, the stent was actually designed for the SFA. The intent from the beginning was that the stent would be robust, durable, and fracture resistant. That is a positive even before adding paclitaxel and a polymer to the stent. In peripheral intervention today, our choices are limited, unless we start talking about using drug-eluting stents. We are going to use a balloon on everything, maybe atherectomy, and it varies, but most people will finish with some sort of antiproliferative therapy. Drug-coated balloons are an excellent therapy, but in patients with long lesions and chronic total occlusions (CTOs), the rate of stent usage is 40-50%. If we are trying to be cost effective in that scenario, we need to start thinking about how to use our tools most efficiently. A long lesion, a calcified lesion, or a long dissection most likely will not remain open with balloon angioplasty alone, even a drug-coated balloon. In my practice, I do initial therapy to open the vessel, whether balloon, atherectomy, or whatever, and then make an assessment of whether I think that vessel is going to remain open after angioplasty with a drug-coated balloon alone. If I think I will need a stent, I will skip the drug-coated balloon and go straight to a drug-eluting stent, usually an Eluvia stent. The appeal of this stent is that it allows me a differentiated pathway to care for the patient during the procedure.

How were longer lesions and CTOs represented in the IMPERIAL trial?

In the pivotal trial, the actual lesion length in the trial was about 9 cm, a reasonably moderate length lesion. IMPERIAL also had a separate non-randomized substudy looking specifically at long lesions, comprised of 50 patients. The lesions in that group were 16 cm on average, about twice the lesion length as in the pivotal trial. The outcomes in those patients were excellent at one year, showing equivalent efficacy and safety to that seen in the main study, demonstrating that Eluvia works well independent of lesion length and lesion complexity.

Would you ever make a decision to mix therapies in a longer lesion or do you typically stick with a single therapy?

Most people will choose a therapy and stick with it. It goes back to the cost effectiveness. If you start pulling out multiple eluting therapies like a balloon and stent, and let’s say you didn’t guess correctly on the balloon, now you have to pull out a stent, so it quickly starts getting expensive. At least in my lab, once the decision is made to move forward on a stent pathway, we typically will use a drug-eluting stent. A drug-coated balloon and bailout bare metal stent is certainly a pathway we can use, but we try to avoid it only because it is not as cost efficient.

Was cost efficiency evaluated in the IMPERIAL trial?

We are actually doing work now on cost effectiveness using the Eluvia data and are putting it into an abstract for the spring meetings. When you look at the dataset, it does look cost effective overall to use Eluvia. We imagine that remains true for the long-term cost, because if you eliminate restenosis or reintervention, it certainly is going to be cost effective. Looking primarily at reimbursement, if a stent is used, reimbursement is a certain amount, and if a drug-coated balloon is used, it is different, lesser amount. However, if a drug-coated balloon plus a stent is used, reimbursement is only for the stent; there is no additional reimbursement for the drug-coated balloon. Eluvia’s benefit is self-evident, I think, when we consider narrowing the cost of the procedure; we are doing some of the work now to analyze that aspect. 

Reprinted with permission from Vascular Disease Management 2019 Dec; 16(12). Copyright 2019 HMP Global.

Disclosures: Dr. William A. Gray reports he is a consultant to Boston Scientific Corporation.

Dr. Gray can be contacted at grayw@mlhs.org.

References
  1. Gray WA, Keirse K, Soga Y, Benko A, Babaev A, Yokoi Y, et al; IMPERIAL investigators. A polymer-coated, paclitaxel-eluting stent (Eluvia) versus a polymer-free, paclitaxel-coated stent (Zilver PTX) for endovascular femoropopliteal intervention (IMPERIAL): a randomised, non-inferiority trial. Lancet. 2018 Oct 27;392(10157):1541-1551. doi: 10.1016/S0140-6736(18)32262-1.
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