Cryoplasty in the Treatment of Infrainguinal Arterial Disease: An Interview with James Joye, DO

Many physicians are exploring device use in the lower extremities, while techniques for successful and appropriate stenting are also being intensely discussed. Where does cryoplasty fit into the current picture?

Peripheral vascular disease, in general, is a relentless and proliferative process. With cryoplasty, whether it be in the fem-pop segment or below the knee, we are trying to achieve both better acute outcomes and long-term outcomes. What we're trying to accomplish is a minimization of the need for stent implants in the legs because they have their own set of problems and simultaneously, we are trying to prolong the patency of these arteries to enhance the results of endovascular interventions. There are whole host of potential applications for this therapy, and the ones easiest to point to are in areas of the lower extremities where a stent solution is not ideal, such as where there is flexion, at the knee or at the hip. These are arteries that we know have a very bad track record with stenting, especially below the knee. For patients like that, this really offers a breakthrough opportunity for treatment. In the U.S. pivotal trial, we had lesions that ranged from very focal simple disease to those that were up to about 10 cm in length and included occlusive disease — so not just stenotic disease. With the below-the-knee work, we were dealing with patients who had critical limb ischemia. They had rest pain, ulcerations and early gangrenous changes, which means fairly extensive disease and obviously it’s a higher risk population of patients. Despite that, we were able to achieve about a 95% rate of limb salvage. In critical practice, physicians who have adopted the technology continue to apply it in a wide range of lesions: longer lengths and lesions that are more complex.

What can you tell us about the recently announced final data in the U.S. pivotal trial?

The U.S. pivotal trial was completed in December of 2002. We have previously reported the 9-month target lesion rate in these patients, which was ~17%. At VIVA, the final data were presented by the director of the ultrasound core lab, Dr. Michael Jaff. Dr. Jaff reported a primary patency rate of 76% with a primary assisted patency rate of 94% at the conclusion of the study. Primary patency included the hard endpoints of patients that required re-intervention, with those that were found to have restenosis by duplex ultrasound in the follow-up period. We continue to try to accumulate longer and longer-term data, and we continue to like what we see.

How far out is patency data?

Our first patients treated now are out about 30 months. In November 2004, in the Journal of Vascular Interventional Radiology,¹ we reported on the initial human experience, which had an 18-month angiographic follow-up (abstract below). In that group, the patency of those vessels by angiography at 18 months was 83.6%.

What do diabetic patient results look like?

Obviously, the diabetic is high on the list of concerns because they have a much higher risk of amputation. Interestingly, in the U.S. pivotal trial, when we broke down diabetic versus nondiabetic patients, they performed essentially the same. In contrast with other therapies that we’ve seen reported over the years, where diabetes always makes things behave worse, the early trend with cryoplasty is encouraging. Even though we are not dealing with thousands of patients in terms of the analysis, it does suggest that this therapy may show particular promise in the diabetic patient. Diabetics, in particular, have a much higher rate of stenosing or occluding stents — that small diabetic vessel just doesn’t do well with an implant because the foreign body response is so aggressive. Similarly, in the limb salvage abstract that we presented at TCT, 85% of those patients were diabetic.² The patient cohort was diabetic by a large majority and they ultimately did much better than they would have in the absence of treatment. As a result, we are definitely in favor of diabetics being steered towards this technology.

Are there patients where you would eventually want to do the same treatment again?

hat’s a good point. It’s actually one of the nice side stories of this procedure. We are not muddying the waters by putting in a metallic implant, because we're trying to leave the artery in its native state. There’s no handcuffing of options should the disease recur, so there’s certainly no limitation to coming back if needed and performing a second, similar procedure. There would be no limitation to applying any of the other therapies that are available or, for that matter, to offering surgical intervention if it was thought necessary. Based on the trial data that we have to date, the good news is that the frequency of the need for repeat intervention seems to be less than plain old angioplasty or stenting.

How is apoptosis contained during use of the system so that the vessel wall is not damaged?

The cold exposure is at the interface of the balloon and the vessel wall or the interface between the balloon and the plaque. The depth of treatment is only about 500 microns, so it’s not a particularly deep therapy. It is deep enough so that it helps to modify the plaque and helps it to dilate and release the plaque in a benign fashion. It is deep enough that it can affect the elastin fibers and reduce recoil. Perhaps more importantly, it is deep enough to signal apoptosis in smooth muscle cells to downgrade that restenosis response. In the variety of the bench and animal testing work that we've done, in hitting that desired temperature of -10 degrees centigrade, we were able to induce apoptosis in about 50% of the smooth muscle cells. That removes a significant percentage of cells that would ultimately contribute to restenosis, but it also removes that group of cells which would signal the recruitment of additional smooth muscle cells. It has a deamplification effect on the whole process.

What is the current status of Below the Knee Chill?

Below the Knee Chill is a multi-center trial that is under multi-disciplinary supervision. Bruce Gray in North Carolina is a vascular medicine specialist, Tony Das in Dallas is an interventional cardiologist, and Tom McNamara at UCLA is an interventional radiologist. They are all the co-principal investigators of this study, which is a prospective, non-randomized registry of patients with critical limb ischemia, rest pain, ulcerations, and/or early gangrenous changes. The goal of the registry is to get a broader look at how these patients behave with cryotherapy. The impetus behind this has had a little bit to do with the technology and a little bit to do with the patient population. The abstract that was presented at TCT (at right) gives us a reasonable footing from which to embark on this type of study. Based on what we saw in the pilot study and based on what we’ve seen in larger vessel treatments in the femoral-popliteal arteries, we have a fair degree of confidence that we will be able to accurately dilate these vessels and leave them in a condition that doesn't require a stenting implant, which traditionally doesn’t behave very well. The whole goal of the therapy and the whole goal of the trial is to prevent major amputation, promote wound healing, and to restore full function. We’re looking a variety of factors related to those parameters over the course of follow up. Approximately 25 centers are involved in the study and we should start to gather initial data in the spring of ‘05.

What’s the typical procedure time and cost for a cryoplasty procedure?

Procedure time varies with the complexity of the lesion. A single treatment or inflation with a cryoplasty balloon is really about a 60-second ordeal. It takes more time to put a wire through the blockage and get the catheter there than it does to actually connect the system, turn it on and make it work. There are cases where we’ll treat over a broad length of the femoral-popliteal segment, which may require repeated, overlapping inflations. Even in those cases, we’re talking about a matter of minutes to deliver the therapy. In terms of cost, it’s on a par with a peripheral vascular stent, so it’s very competitive in that respect. The financial story actually gets increasingly better with more aggressive disease. In a stent approach, where you’re dealing with a 30-cm-long segment of disease, you normally have to put in 3 or 4 stents and use 2 or 3 balloons. The cost just for product use can get in the $10,000 range pretty easily. In contrast, with a cryoplasty approach, you might end up using a couple of catheters and a series of nitrous oxide cylinders. The overall cost is probably in the range of $2000 to $2500. In a more simple procedure, $1500 or thereabouts is about all that is incurred in product costs.

What type of training is necessary for physicians interested in using the PolarCath System?

Cryoplasty does not necessarily deviate in any dramatic fashion from conventional interventional practices. It’s very similar to angioplasty in its application. It does not necessarily require formal additional training other than just an introduction to the device and pre-procedural review of the technology — how to plug it in and play it, basically. The passage of the catheter to the desired location is the same as with conventional angioplasty. It just uses a different inflation medium and a slightly different inflation unit.

Could you talk about the history behind cryoplasty and the PolarCath?

The history, at least intellectually, dates back into the late 1960’s and early 1970’s in the field of cryosurgery. At the time, there was a heavy onset of minimally invasive surgery using cryoprobes to treat tumors. Cold, at extreme temperatures, has a very good effect on eliminating unwanted tissue. Most tumors are very vascular and there were concerns as to what the integrity of those blood vessels would be in the aftermath of cold exposure. As a result, there was a series of elegant trials performed which showed very nicely that blood vessels, in particular, arteries, are very immune to any adverse effects from cold, and in fact have a very limited proliferative response to that cold exposure. The thinking was that if this is a relatively benign bodily response to cold and we can superimpose that time period when we know if we dilate and stretch an artery, we’re going to induce inflammation and proliferative response, then perhaps we can attenuate that response and improve late term outcomes by combining dilation and freezing simultaneously.

Can you describe your involvement in the process?

It began back in 1997 with my co-founder, Ron Williams. I had worked with his wife on a different device venture (she does clinical research). She knew that I was putting together some thoughts and ideas on a project, and Ron had been very successful in a number of different engineering efforts in the device world. His wife basically put the two of us together — the classic back-of-the-napkin story. We had a dinner, we met each other, we talked about the ideas. I threw a couple of things on a piece of paper and he looked at me and thought that I wasn’t too crazy, so we were off and running. We pooled the limited resources we had at that time and incorporated a company, built some prototypes, did some initial animal work and based on those early findings, we were able to generate a significant amount of venture capital interest and ultimately, corporate interest. For the past seven-plus years now, we’ve launched from what was very much a garage experience to a facility that is mass manufacturing and supports a large head count.

Where is the cryoplasty procedure in terms of CMS reimbursement?

We have met with CMS and delivered the message, and they’re in the consideration mode. We have full reimbursement at present under angioplasty guidelines, so it’s a reimbursable technique. We’re just trying to take it to the next step and identify it as a separate, superior technique so that we can remove any potential barriers to product use for patients that may be based only on that reimbursement scheme.

What do you see as the future of cryoplasty?

I think the focus will remain predominantly peripheral vascular. As with any emerging technology, as time passes, we understand better where the device is best utilized. I think it will always have a place in infrainguinal lower extremity disease. There are a couple potential areas of interest. What is not really openly discussed or considered at this point is the treatment of patients who have stenoses below the knee, but do not have critical limb ischemia. We tend to treat those patients very conservatively. We watch them and wait until they get into trouble before treating them. If, on the other hand, we had a therapy that effectively treated those vessels and kept them open longer than natural history would otherwise allow, then we might be able to really expand the scope of application to a much broader group of patients. Similarly, we are looking into some larger-scale work that will evaluate the value of cryoplasty in patients who have previously placed stents that have restenosed. We do have some abstract data that shows some favorable results, but we need to expand our work in this area. Is there synergy between cryoplasty and some other devices out there? There are a number of centers and physicians who are doing simultaneous atherectomy and cryoplasty, which I would have to admit is a very attractive method for treating the most advanced disease that we see, and at least has some very favorable acute outcomes. Whether there is potential synergy in a patient that requires a stent is yet to be determined. So you can see there are a whole other host of permutations that we have to explore. Peripheral vascular treatment aside, we're also in the process of going forward with coronary CE-marking in Europe and may also pursue a coronary indication in the US as well. The potential for such a therapy in the drug-eluting stent world is really the big question mark right now.

Dr. Joye can be contacted at: jimjoye@aol.com

Abstract

Cryoplasty for Femoropopliteal Arterial Disease: Late Angiographic Results of Initial Human Experience

Mario Fava, MD, Soledad Loyola, MD, Antonios Polydorou, MD, Prodromos Papapavlou, MD, Adamandia Polydorou, MD, Oscar Mendiz, MD and James D. Joye, DO From the Universidad Catolica (M.F., S.L.), Santiago, Chile; General Hospital of Nikaia Piraeus (Antonios P., P.P., Adamandia P.), Athens, Greece; Fundacion Favaloro (O.M.), Buenos Aires, Argentina; and El Camino Hospital (J.D.J.), Mountain View, California.

Abbreviations: ABI = ankle-brachial index, PTA = percutaneous transluminal angioplasty

Purpose: A new form of angioplasty, called cryoplasty, was developed to improve the late results typically associated with percutaneous transluminal angioplasty. Cryoplasty combines the dilation force of percutaneous transluminal angioplasty with the delivery of cold thermal energy to the vessel wall. This study reports the authors’ early clinical experience with cryoplasty in patients with femoropopliteal disease. Materials and Methods: Fifteen patients with femoropopliteal arterial lesions were treated with cryoplasty (CryoVascular Systems, Los Gatos, CA). Cryoplasty was performed at 6 atm of pressure and delivered at -10°C for 60 seconds. The ankle-brachial index (ABI) was measured at baseline, 24 hours after cryoplasty, and at 1 and 3 months during follow-up. Repeated angiography was performed at 6 and 18 months to determine short-term and late primary patency. Results: Cryoplasty was technically successful in 93% of patients (< 30% residual stenosis and less then grade C dissection). ABIs at baseline were 0.64 ± 0.08 and improved the day after cryoplasty to 0.95 ± 0.09 (P < .05). ABIs were well maintained at 1 and 3 months with measurements of 0.94 ± 0.09 and 0.92 ± 0.10, respectively (P < .05 vs baseline). Baseline angiographic diameter stenosis improved significantly immediately following cryoplasty (86% ± 12% to 16% ± 3%; P < .05). Angiography at 6 months revealed 0% binary restenosis and insignificant change in residual stenosis from the acute cryoplasty results (16 ± 3% vs 21 ± 5%; P = NS). Late angiographic follow-up at 14 months ± 4 demonstrated primary patency of 83.3%. Conclusion: Cryoplasty was able to achieve substantial dilation of femoropopliteal lesions with well-preserved late angiographic patency. Cryoplasty represents a potential advance in the field of endovascular medicine. Reprinted with permission from the Journal of Vascular and Interventional Radiology 15:1239-1243 (2004).

Abstract

Cryoplasty for Critical Limb Ischemia: Initial Below-the-Knee Results

M. Moran, Stanford University Medical Center; J. Joye, The Cardiovascular Institute; F. St. Goar, El Camino Hospital

Background: Critical limb ischemia is an ever-growing problem that accounts for nearly 200,000 amputations on an annual basis. Endovascular approaches have demonstrated the ability to markedly improve limb salvage rates. Cryoplasty has been shown to produce excellent acute- and long-term results in femoropopliteal arterial lesions, but has not yet been evaluated for below-the-knee disease. We report on our initial experience using cryoplasty for critical limb ischemia. Methods: We treated 26 lesions in 20 patients (6 women, 14 men) who presented with rest pain and/or ischemic ulceration and gangrene. The mean age of the patient cohort was 72 + 7 years, and 17 or 20 (85%) had diabetes. Lesions treated were located in the anterior tibial artery (10), tibioperoneal trunk (7), posterior tibial artery (6), and peroneal artery (3). The primary treatment method for all patients was cryoplasty performed at 8 atm and -10?C. A total of 6 patients had adjunctive pretreatment with atherectomy using either excimer laser or excisional atherectomy. Outcomes were evaluated for acute technical success (<50% residual stenosis and continuous in-line flow to the foot) and limb salvage with freedom from major amputation. Results: The technical success of cryoplasty in this patient cohort was 95%; 1 patient failed to achieve the desired acute result and underwent a below-the-knee amputation. Limb salvage with freedom from major amputation was achieved in 95% of the patients treated; 5 patients underwent to or transmetatarsal amputation of pre-existing gangrene, and 1 patient who was treated for bilateral disease underwent subsequent femorotibial bypass surgery. Conclusion: Cryoplasty resulted in excellent acute procedural success and ultimately yielded limb salvage in a high percentage of patients treated. Pending further study, cryoplasty may prove to be a valuable option in the treatment strategy for patients with critical limb ischemia.

Reprinted with permission from The American Journal of Cardiology 94(6):7E (TCT Abstracts Suppl. 2004).