Disclosure: Dr. Dippel reports consulting fees/honoraria: Abbott Vascular, Boston Scientific, Covidien, Spectranetics; major stock/shareholder: Spectranetics.

Dr. Eric Dippel can be contacted at dippel@cvmedpc.com.

EXCITE ISR is the first large, prospective study to examine the effectiveness of laser atherectomy in the treatment of femoropopliteal in-stent restenosis. The trial was designed to enroll a maximum of 318 subjects at up to 40 sites, randomized 2:1 treatment to control with predetermined statistical analyses at 200, 250 and 300 enrolled patients. Earlier this year, Spectranetics announced success of the trial based on achieving highly significant statistical superiority in both safety and efficacy among 250 patients. The treatment arm was laser atherectomy combined with percutaneous transluminal angioplasty (PTA) and the control arm was PTA alone. The primary efficacy endpoint is freedom from target lesion revascularization (TLR) through six months. The primary safety endpoint was freedom from major adverse events (MAEs) at 30 days, including all-cause mortality, major amputation in the target limb, or TLR.

Major inclusion criteria included in-stent restenosis target lesions ≥40mm, vessel diameter between 5-7mm, and Rutherford class one to four. A total of 169 subjects were enrolled in the treatment arm (laser atherectomy and PTA) and 81 patients enrolled in the control arm (PTA alone).

Both groups were similar in baseline demographics and lesion characteristics. Lesion length averaged 190mm and more than 30% of patients presented with total occlusion. Compared to PTA alone, laser atherectomy with PTA demonstrated superior procedural success (93.5% vs 82.7%, P=0.03). Freedom from TLR at six months was 73.5% for the laser atherectomy + PTA group compared to 51.8% for the PTA group (P<0.005). The 30-day MAE rates were 5.8% for the laser atherectomy + PTA group compared to 20.8% for the PTA group (P<0.001).

Can you describe the problem of femoropopliteal in-stent restenosis?

Approximately 30-40% of these stents are going to restenose in about two years. In this country, there are probably over 250,000 stents being put into the femoropopliteal arteries per year, so over time, we are probably dealing with 100,000+ cases of in-stent restenosis. It is a big problem. We have patients that just keep coming back and needing treatment. Once they start to restenose, it seems like they keep restenosing. An important thing about EXCITE ISR is that it is a randomized study. There haven’t been any other randomized studies looking at this problem, and there is no current, optimally defined treatment for in-stent restenosis. 

The thing about restenosis is that the tissue is about 85% extracellular matrix and only about 15% cellular material. It has a very high water content. People may blow up a balloon, take a picture and see that it looks good, and then walk out patting themselves on the back, thinking that their patient is cured. Albertal et al did a study about 15 years ago looking at coronary angioplasty for in-stent restenosis.¹ They did intravascular ultrasound before and after the procedure, and then had the patients come back after ~30 minutes had passed for restudy. Basically what they showed is that angioplasty just compresses the water out of the tissue, which then just rehydrates, and so the restenosis comes back right away. Balloon angioplasty doesn’t work for in-stent restenosis, but there has never been a systematic approach to looking at it. EXCITE ISR is the first study to systematically try to address that question.

What are some of the things people have been trying?

They will use a plain balloon, different types of atherectomy, Cutting Balloons (Boston Scientific), restent it, or try combinations of different devices. But there has been no systematic way of trying to find how to treat this problem.

How did laser atherectomy plus PTA fare in the trial endpoints?

Laser is a safer procedure with better outcomes. The primary safety endpoint was death, revascularization and major limb loss, very statistically positive at 94% versus 79%, favoring the laser. The safety endpoint was at 30 days. The efficacy endpoint was at 6 months, and that was freedom from target lesion revascularization, which was also very positive in favor of the laser at 74% versus 52%. Laser is a safer procedure than a balloon, the acute procedural success rates were higher with the laser, there were less dissections, and there was less bailout stenting at 4% versus 11%. 

How does laser atherectomy work?

Laser works by photoablating tissue. It uses light energy to disrupt the molecular bonds between cells and vaporizes tissue. It works very well for neointimal hyperplasia because it is relatively soft tissue. Laser atherectomy also works very well for ablating thrombus, and so that combination makes it almost perfect for in-stent restenosis. There are different diameters of the laser catheters, and they just ablate right at the very tip. So a 2.0mm laser will make maybe a little more than a 2mm channel. To address this issue, a few years ago, Spectranetics launched an offset laser on a support catheter, called the Turbo-Tandem catheter. As you make passes and rotate it, the Turbo-Tandem laser catheter makes an eccentric cut, allowing for bigger cuts. You do the first pass with the pilot catheter, the Turbo Elite catheter, and then use the Turbo-Tandem catheter to make eccentric cuts and achieve a bigger lumen.

How many passes are typically made with the laser (both the pilot Turbo Elite and the Turbo-Tandem)?

As far as making the pilot channel, it hasn’t been that well defined. There are some people that think if you make several passes you will get an incremental improvement in the size. I usually try and make two, but some people may do one. With the Turbo-Tandem catheter, which is the offset laser, you can go more around the clock face, if you will, and get more debulking. We try to recommend at least 4 passes, but if people want to make more, they can. 

It’s interesting that you said the laser “vaporizes” tissue, which brings up the issue of distal embolization.

Yes, that’s what people talk about quite a bit. What’s the embolization rate? We’ve published data on this in the past with a variety of different devices, including balloons, stents, and different atherectomy devices. The long and the short of it is that all devices embolize to some degree. Some may do so more than others. With the laser, it tends to embolize tiny cell fragments, almost powdery or pasty stuff. It is not large chunks. There is some cellular debris that goes downstream and so I routinely use filters on all my cases. Not just for the laser, but I routinely use embolic protection. I have always felt that filters are like the seatbelt of intervention. It is not routine and many centers don’t use filters. That is just a practice pattern. In this study, we didn’t mandate that filters be used and it was left up to the discretion of the operators. Embolic protection was used about 30-40% of the time.

You emphasized in your TCT presentation that EXCITE ISR enrolled very real-world patients.

Yes, that was one thing I was very insistent on from the beginning, because I am frustrated with certain clinical trials that are very non-real-world. They don’t apply to what I do, what the person next to me does, or what the person at another hospital does. These clinical trials enroll very simple cases that are not remotely anything like what you see in the real world. So I was very insistent from the beginning that the trial be very liberal in terms of who would be allowed in the study. We wanted to try and take all comers as much as we could, within certain confines. One important aspect was the lesion length, because the superficial femoral artery (SFA) is 30+cm long. It would not be right to limit the trial to just short lesions. In this study, the average lesion length was 19cm, longer than any study that has been done in the periphery thus far. Over 30% of those cases were chronic total occlusions (CTOs), and 20% of the lesions were over 30cm in length, meaning the entirety of the leg. So a lot of these were very difficult cases. 

It is also important to note that these data cannot be extrapolated to other atherectomy devices, because some of them have relative contraindications to being used in a stent, maybe grabbing or getting tangled up in the stent strut. Those studies would have to be done individually to prove that they are safe. 

What signals were sent with laser atherectomy vs PTA before this trial was begun?

Spectranetics did the first study in Europe, a non-randomized feasibility study called PATENT², which looked at treating patients with laser atherectomy for in-stent restenosis. Those results were very favorable, and led into the randomized trial in the United States that actually compared laser atherectomy to plain balloon angioplasty. 

EXCITE ISR was the first trial looking at an atherectomy device for in-stent restenosis.

Yes. The studies out there are mostly a series of patients or registry patients, not randomized studies. EXCITE ISR is a randomized study, and I think that is why it was so well received, because you typically don’t see that in peripheral vascular disease. In cardiology, there are lots of randomized studies for things like cholesterol, heart failure, and coronary artery disease that have ten, twenty, thirty thousand people. Peripheral studies are non-randomized with twenty, thirty or a hundred people. We wanted to create Level 1 evidence and say, if balloon is considered the gold standard right now, is laser atherectomy better? I think we proved that it is, and the trial results provide a new defined treatment strategy for in-stent restenosis. At least that is a starting point. Drug-coated balloons could be complementary; I’m not sure they are necessarily competitive. I don’t think we should view it that way. 

What is the next step?

Looking at laser atherectomy with a drug-coated balloon afterwards. That makes a lot of sense to me and I think it will probably push the window to treatment back even farther. I doubt it will be a cure. Patients want to come in, have one procedure, and never come back again. It doesn’t work that way, unfortunately. If we can push it back so they don’t have to come in every 3, 6, 12 months, that would be ideal. Once that stent is in there, you can’t take it out. A lot of people believe stents are a nidus for inflammation and recurring scar tissue, and the restenosis is just going to keep returning. Probably the biggest focus right now is just debulking that tissue and then putting some kind of drug in there to keep it from coming back. That is where I see things going.

What about paralleling the use of intracoronary bolus in the periphery?

We have actually looked at that and done some studies using a drug delivery device. We have done a few small series of patients and I think it would be helpful, but there are some technical issues on getting the drug where it needs to be and other things that would need to be worked out.

Drug-coated balloons might solve those problems. 

Yes, it’s kind of a race between the two. 

Where are you now with the EXCITE ISR follow-up? 

The TCT presentation was the first presentation of any of the trial data. We have about two-thirds of the patients to their 6-month endpoint and a third of the patients to the one-year endpoint, so the complete follow-up is not yet done.

Any final thoughts?

When you look at patients with in-stent restenosis, once they get it, it keeps coming back. So these people are not ever really cured of their disease. It is disease management. Instead of coming into the hospital every three months to have a balloon dilated, maybe it could move to every 6 months, a year, or even 5 years — just extend the time to treatment further out. That is the goal. I would like to think we are curing people of this problem, but we are not curing them, we are just changing the management strategy.

The results of the EXCITE ISR study led to the FDA approval of the Turbo-Tandem catheter to be used for in-stent restenosis, so that’s landmark to me in itself. I would like to give credit to both Spectranetics and the trial co-investigators, because there was a lot of hard work and dedication on their part.

References

1. Albertal M, Abizaid A, Muñoz JS, et al. A novel mechanism explaining early lumen loss following balloon angioplasty for the treatment of in-stent restenosis. Am J Cardiol. 2005; 95: 751-754.
2. Schmidt A, Zeller T, Sievert H, Krankenberg H, Torsello G, Stark MA, Scheinert D. Photoablation using the turbo-booster and excimer laser for in-stent restenosis treatment: twelve-month results from the PATENT study. J Endovasc Ther. 2014 Feb; 21(1): 52-60. doi: 10.1583/13-4538R.1.