Author + information
- Anand Prasad, MD⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Anand Prasad, Department of Medicine, Division of Cardiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78229
Over the past decade there has been an explosion in the number of tools available for the endovascular treatment of lower extremity peripheral arterial disease (PAD). Seemingly every few months, the interventionalist is confronted with a new device that promises to deliver both immediate angiographic improvement and long-term freedom from restenosis. Despite the increasing availability of newer angioplasty balloons, nitinol stents, drug-coated devices, and atherectomy cutters, the ideal treatment for an individual patient is unclear and often not based on rigorously vetted data. In contrast to the coronary circulation, this clinical uncertainty is largely the result of a paucity of randomized controlled trials to evaluate the utility of these devices.
In this issue of the Journal, Banerjee et al. (1) present data from a prospective multicenter randomized controlled pilot trial (COBRA [Cryoplasty or Conventional Balloon Post-Dilation of Nitinol Stents for Revascularization of Peripheral Vascular Segments]) to examine the benefit of cryoplasty in diabetic patients using the PolarCath peripheral dilatation system (Boston Scientific, Natick, Massachusetts) as an adjunctive treatment after nitinol stent placement in the superficial femoral artery (SFA). Cryoplasty using this system has been approved since 2004. The widespread adoption of this technology has been limited by mixed clinical data and a lack of fundamental understanding of cryobiology in relation to PAD. In comparison to drug-eluting balloons, for example, where the biology of paclitaxel has been studied extensively, the mechanisms underlying vascular responses to cryoplasty have lagged behind the clinical implementation of this tool.
Mechanisms of action
Cryoplasty (using the PolarCath) is hypothesized to have 2 pathways of action on peripheral vessels. First, there is the standard effect of plaque disruption and vessel dilation using low pressure inflation. This microprocessor-controlled dilation is suggested to induce less mechanical barotrauma than conventional angioplasty. Of course, while a “low and slow” inflation may prevent trauma and dissection, it may also limit acute gain and result in restenosis or reocclusion. Therefore, the second and more interesting aspect of this device is the delivery of liquid nitrous oxide into the balloon system. As the liquid changes phase to a gas, the balloon inflates and the associated heat transfer results in supercooling of the balloon to −10°C. As already mentioned, the physiological impact of cooling on the vascular architecture remains an active area of study. However, several mechanisms have consistently emerged in multiple studies—mostly performed using animal-derived tissue and cell preparations (2–5). The pathway of most biological relevance is apoptosis of vascular smooth muscle cells with relative sparing of the endothelial cells. This process is hypothesized to limit the inflammatory and reactive responses to injury that often follow angioplasty, leading to restenosis. Some data would suggest that both the rate and magnitude of cooling directly impact the depth of treatment within the vessel wall as well as the relative balance between necrosis and apoptosis (5). However, the duration and magnitude of smooth muscle cell suppression in humans undergoing cryoplasty remain poorly defined.
Clinical data for use of cryoplasty in humans
The various studies that have examined the clinical utility of cryoplasty for PAD in humans are highlighted in Table 1 (6–22). The majority of these studies have consisted of nonrandomized single-center experiences. Accordingly, the patient population, methods, and outcomes have varied considerably. In most studies, the acute angiographic success rates have been excellent; however the long-term rates in regard to patency or target lesion revascularization have been inconsistent—comparable (or worse in some studies) than conventional percutaneous transluminal balloon angioplasty (PTA). The handful of small randomized trials to date have also not demonstrated an overwhelming benefit of cryoplasty over PTA. In all of these trials, cryoplasty was looked to as a primary endovascular treatment (with stenting reserved for bail-out). Therefore, underlining these trials are basic mechanical limitations of PTA that are shared by cryoplasty, namely, vascular recoil and dissection. Placement of nitinol stents solves the problems associated with acute recoil and dissection, but continues to invite the bane of restenosis. Accordingly, the benefits of routine stenting over PTA alone have been decidedly mixed in the literature. It is with these limitations in mind that the COBRA trial makes sense: use a stent to counter the acute mechanical limitations of PTA, and use cryoplasty to address the smooth muscle mediated restenosis process.
What did we learn from the COBRA trial?
Banerjee et al. (1) used the aforementioned framework to perform a pilot study of SFA nitinol stenting followed by post-dilation with cryoplasty versus conventional balloon PTA. Forty-five patients were randomly allocated to each group, and notably, despite the small sample size, the 2 groups were fairly well matched in terms of comorbid conditions. The investigators used binary restenosis as their primary endpoint, defined by a ≥2.5-fold increase in peak systolic velocity within the stented segment. Patients in the cryoplasty arm had PolarCath treatment once the nitinol stent was in place as the final post-dilation treatment or after conventional post-dilation. The entire length of the stent was treated with cryotherapy. The key finding of the study was a significant difference in the 12-month binary restenosis rates (55.8% in the PTA arm and 29.3% in the cryoplasty arm, p = 0.01). Furthermore, as a secondary endpoint, there was a sustained improvement at 12 months in the ankle-brachial index in the cryoplasty group that was not seen in the conventional PTA arm.
Given the unique post-dilation cryotherapy strategy of the COBRA trial, it is difficult to directly compare these data with previous studies in the literature. However, 2 randomized studies have examined cryoplasty specifically in diabetics. Spiliopoulos et al. (6) performed a small single-center randomized trial of cryoplasty (n = 24) versus conventional PTA (n = 26) involving diabetic patients with Rutherford stage 3 to 6 symptoms for femoropopliteal disease. In this particular study—as in all the prior randomized cryoplasty trials—stenting was used only for bail-out (26% usage in cryoplasty arm). A particular strength of this trial was the use of invasive follow-up and an angiographically determined binary restenosis definition. Immediate technical success rates were relatively low: 58.0% in the cryoplasty arm and 64.0% in the PTA arm (p = 0.29). The researchers found that in-lesion angiographic binary restenosis was significantly higher with cryoplasty at follow-up as compared with PTA. On multivariable analyses, cryoplasty was associated with increased TLR events and decreased vessel patency. Fossaceca et al. (21) also compared PTA to cryoplasty in 48 diabetic patients with femoropopliteal disease in a prospective randomized trial. Echoing the general findings of the study by Spiliopoulos et al. (6), the investigators found that cryoplasty resulted in both an intermediate (6 months) and a longer term (12 months) decrease in vessel patency as well as a lower rate of initial technical success. Furthermore, they noted more pain during inflation with cryoplasty as compared with PTA—a phenomenon that is not universally commented on in other trials.
Given the small sample sizes, it is difficult to draw definitive conclusions, but these data involving diabetic patients would suggest that, at a minimum, cryoplasty as a primary strategy is not a better treatment than traditional PTA. The results, however, do add to the rationale for the COBRA trial. Stenting often provides a better acute procedural result than PTA alone, and can improve the immediate technical success in complex calcified and diffusely diseased vessels as seen in diabetic patients. With mechanical scaffolding in place, cryoplasty can then be considered as an adjuvant therapy to deter restenosis.
Limitations of the COBRA trial and future strategies for restenosis prevention
The findings of the COBRA trial should be taken in the light of a preliminary study. As a small trial, there were several notable limitations. First, the authors chose to study only diabetic patients. Although the burden, severity, and poor outcomes of PAD in diabetic patients are well documented, inclusion of a more varied patient population would have allowed for a larger study and more generalizability to the general PAD population. Second, as an inherent limitation of a small pilot study, it is not possible to know if the strategy of post-dilation employed in the study will lead to any true difference in clinical outcomes. Interestingly, both groups had an improvement in mean walking impairment scores even though the significant improvement in binary restenosis and the ankle-brachial index was confined to the cryoplasty arm. Third, the lack of angiographic follow-up in all patients limits the anatomical analyses in regard to stent fracture, collateral formation, and progression of plaque. Last, we cannot predict where the strategy outlined in the COBRA trial will fit in with the current and upcoming endovascular treatments for PAD. With the concerns of stent fracture and restenosis, many interventionalists have migrated away from stenting. In this regard, the role of primary debulking before additional treatments will have to be evaluated, as will the role of biodegradable technologies. In addition, the relative efficacy of cryoplasty versus drug-eluting balloons for post-dilation of nitinol stents will need to be studied.
Widespread adoption of this technology will also be helped by a better understanding of the vascular biology of cryotherapy. What is clear is the need for further funding and interest in performing randomized controlled trials for PAD revascularization. In this regard, Banerjee et al. (1) should be commended for their novel approach to a challenging problem.
Dr. Prasad has reported that he has no relationships relevant to the contents of this paper to disclose.
↵⁎ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
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