IMPERIAL: Slow-Eluting Stent Outpaces Standard for Fem-Pop Lesions

Patrice Wendling

September 22, 2018

SAN DIEGO — A novel stent with sustained paclitaxel release showed superior target-vessel patency at 1 year against the standard paclitaxel-eluting stent for treatment of femoropopliteal artery lesions, in the first such head-to-head comparison.

The independently adjudicated 12-month primary patency rate was 86.8% for Eluvia (Boston Scientific) and 77.5% for Zilver PTX (Cook Medical).

This met the 10% noninferiority margin set for the Eluvia Drug-Eluting Stent Versus Zilver PTX Stent (IMPERIAL) trial (P < .0001) and prompted a prespecified post hoc analysis for superiority, which also was achieved (P = .0144).

In addition, patients treated with Eluvia rather than Zilver PTX had half the rates of clinically driven target lesion revascularization (TLR; 4.5% vs 9%; P = .0672) and stent thrombosis (1.7% vs 4.0%; P = .1956), according to late-breaking results presented here at Transcatheter Cardiovascular Therapeutics (TCT) 2018 and simultaneously reported in The Lancet.

"There were no safety signals, it was clearly effective — at least as effective, and more effective frankly than the predicate — so I'd be shocked if it didn't get approved,'' principal investigator William A. Gray, MD, Lankenau Heart Institute, Wynnewood, Pennsylvania, told theheart.org | Medscape Cardiology.

The multinational, noninferiority trial was designed to support US approval of Eluvia, which received a CE mark in 2016.

Gray noted that Eluvia has a biostable fluorinated polymer matrix that releases paclitaxel out to 1 year, while the polymer-free Zilver PTX rapidly delivers paclitaxel that remains in arterial tissue through 2 months. Restenosis in femoropopliteal lesions typically peaks between 9 and 10 months, he said; thus, "the intent was to stretch out paclitaxel elusion to better match the biology of restenosis."

IMPERIAL enrolled patients with chronic lower limb ischemia (Rutherford class 2 - 4) and proximal superficial femoral artery (SFA) and popliteal artery  lesions between 30 and 140 mm with at least 70% stenosis and randomly assigned 309 to Eluvia and 156 to Zilver PTX.

Mean lesion length was 86.5 mm in the Eluvia arm and 81.8 mm in the Zilver PTX arm. Moderate to severe calcification was present in about 60% of patients in both arms and total occlusion in about a third of lesions.

At 12 months, 89.6% of patients treated with Eluvia maintained improvement by at least one Rutherford category without TLR, as compared with 83.1% of those treated with Zilver PTX (P = .0571). No or minimal symptoms (Rutherford 0 - 1) were reported in 85.8% vs 84.5%, respectively.

Ankle-brachial index improved in most patients, though the difference was not significant between groups, while walking impairment improved significantly from baseline in both groups.

"The important difference is that it took about twice as many TLRs in the Zilver group to achieve these results," said Gray.

Following the presentation, Michael R. Jaff, DO, president of Newton-Wellesley Hospital, Newton, Massachusetts, said he was particularly struck by this finding, because the goal for his patients with claudication is to see them walk better and for longer periods of time without needing a repeat intervention.

"Now if I put my hospital president's hat on, that's a good thing too because all the money, all the cost-effectiveness in these vascular device trials lives with the cost of repeat interventions," he said. "So the fact that we can get excellent clinical outcomes at a lower cost, that just rings all the way across."

Panelist Sahil A. Parikh, MD, New York-Presbyterian Hospital/Columbia University Medical Center, New York City, said halving the TLR rate was compelling, but "as an interventionalist, we've been using a lot of drug-coated balloons in the SFA in the last 5 years in the United States, in addition to Zilver, and now the fact that with 60% calcific patients we can get a TLR rate in the single digits, I think is just spectacular."

"I think it will open a new era for us in stenting the SFA."
 

Some Caveats

Panelist Gary M. Ansel, MD, Ohio Health, Riverside Methodist Hospital, Columbus, also praised IMPERIAL but said, "The only caveat is that these are 1-year results. Zilver PTX has 5-year results, and the early attempts at a polymer-based stent fell off after that first year. So all these things have to be weighed in perspective as we go forward."

Long-term results reported last year from the single-arm, first-in-human MAJESTIC trial showed a primary patency rate of 83.5% at 24 months with Eluvia in patients, with suboptimal results after balloon angioplasty.

A Kaplan-Meier analysis of primary patency in IMPERIAL showed no dropoff at 12 months for Eluvia vs Zilver PTX (88.5% vs 79.5%; log-rank P = .0119), Gray said.

The major adverse event rate was noninferior for Eluvia vs Zilver PTX (4.9% vs 9.0%; P = .0975), driven by the lower stent thrombosis rates. There were no deaths at 1 month in either arm; major amputations occurred in 0.3% of patients with Eluvia and no patients with Zilver PTX.

There were six cases of positive remodeling with Eluvia (2.1%), although all six lesions were patent at 1 year and none had TLR or stent thrombosis, Gray said.

Still, this prompted the panel to question its implications and potential for aneurysm formation, which has been reported elsewhere with Eluvia.

"It doesn't look like it's due to aneurysm because there's not flow around the stent and there seems to be a flow void there," said Gray.  "I'm buoyed by the fact that there's been no safety or efficacy events and it's in very low numbers."

Nonetheless, the reports prompted the investigators to undertake a detailed analysis at 12 months, which they plan to repeat at 24 months. "You can speculate all day as to what it's caused by, but again I take heart of the fact there are no safety and efficacy issues."

But What About Reimbursement?

Despite the use of drug-coated balloons (DCBs) as part of the 'leave-no-metal behind' mindset, Gray speculated to theheart.org | Medscape Cardiology that the results "will probably move the practice towards greater use of drug-eluting stents."

"Since we have patency numbers which are at least as good or better than DCB, I think we're looking at a streamlined procedure where people will choose, especially in the more complex lesions — longer, calcified, dissected — to move quickly to a solution which is most expedient, gives the best angiographic result, and clearly has durable results and outcomes," he said.

Commenting to theheart.org | Medscape Cardiology, Parikh said longer-term follow-up is needed to monitor the positive remodeling effect but that operators will adopt the new technology, especially since the trial had patients with calcified lesions, the "Achilles heel of a balloon-based strategy."

"I think the days of full-metal-jacket stenting as the standard of care are gone because we do have excellent drug-delivery technologies that allow you to avoid metal when possible, but now we actually have a great alternative when we can't avoid metal," he said.

"One of the huge unknown questions," he said, "is what is the reimbursement going to be?"

Zilver PTX has never gotten an add-on or master payment code like DCBs did, and adoption of the technology has flattened with the loss of the pass-through payment for DCBs, noted Parikh.

Also, about 30% of peripheral arterial interventions now are done in ambulatory surgical centers or office-based laboratories, where atherectomy is highly reimbursed and consequently penetration is nearly 95%. Conversely, the penetration of DCBs is maybe 3% to 5%, he said, whereas uptake in the hospital outpatient setting, where there was a pass-through payment, was 30% to 40%.

"That delta cannot be explained by any data, and the suspicion, or the elephant in the room, is that it's because of the differential motivations of what kind of reimbursement structure is in place," Parikh said. "I fear that as we move even further into the office-based laboratory as a venue of care, that the reimbursement strategy that CMS and everyone else who follows them adopts, will have a big impact on the uptake of this breakthrough technology."

Cost will also be important, as Eluvia will likely be priced higher than a standard nitinol stent.

"I anticipate what's going to happen is that vessel preparation will be the calling card — that in order to achieve adequate drug delivery we need to do some sort of atherectomy," Parikh said.

Asked about this possibility, Gray responded, "I don't agree with that at all…. I think that depends on how tightly you're tied to the RVU wheel."

Moreover, there is an independent code for stent reimbursement in addition to the four bundled payments for femoropopliteal treatment, and in many states, including his home state of Pennsylvania, office-based laboratories (OBLs) are not allowed.

"I acknowledge that a lot of the therapy now is moving to the OBL or ASC [ambulatory surgery center] environment, but whatever we promote here for the patient care has to be reimbursed in both environments."

Gray is an advisor to Boston Scientific, which funded the trial. King reports having no relevant financial relationships. Parikh reports that he or his spouse have received grant support/research contract from TriReme, Shockwave, and Surmodics; received consultant fees/honoraria/speaker's bureau from Terumo Medical or Heartflow; and received other financial support from Abbott Vascular, Boston Scientific, Medtronic, Philips, and CSI.

Transcatheter Cardiovascular Therapeutics (TCT) 2018.

Lancet. Published online September 22, 2018. Full text

Follow Patrice Wendling on Twitter: @pwendl. For more from theheart.org, follow us on Twitter and Facebook.

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