Discussion Question: Will Drug-eluting Stents Have a Major Impact in Prevention of Restenosis After Noncoronary Interventions?

Drug-eluting stents (DES) have revolutionized the treatment of obstructive coronary disease and expanding their applications to the periphery is inevitable.

However, a better understanding of stent-associated restenosis in the periphery is needed. 1) The restenosis rate is very different in various vascular beds and clearly very high in infrainguinal vessels. The superficial femoral artery is probably the vascular bed that will be most in need of DES technology, given its long lesions and high restenosis rate. 2) The restenosis process in the periphery appears to continue beyond the six-month mark that interventional cardiologists are used to in the coronary vasculature. This is now seen in both renal and femoral vessels. DES technology will need to take this into account, which might explain why a slow drug release might be better than a rapid release, as was seen in the SIROCCO trial. 3) A large percentage of patients with peripheral vascular disease have elevated baseline inflammatory markers and exhibit a significant rise in inflammation markers post intervention, which appears significantly higher in the SFA than the iliacs or carotids, and could partially explain the higher restenosis rate seen in the former. Adjunctive therapy to reduce this inflammatory process in addition to stenting might prove very beneficial and might change how DES stents will be used in the periphery. 4) Vessel sizes in the periphery are typically larger than the coronary. The optimal dose, timing and duration of drug elution needs to be determined to provide long-term effectiveness with no or minimal toxicity. 5) A random use of DES in the periphery might not be cost effective, and a clear algorithm is needed as to when and where this technology should be utilized. For instance, large renal vessels carry a low rate of restenosis, whereas small renal vessels. Nicolas W. Shammas, MS, MD, Research Director, Midwest Cardiovascular Research Foundation Davenport, Iowa shammas@mchsi.com

The short answer to this question is “yes.” The explanation is simple and concise. The field of peripheral vascular interventions is still in its infancy. We currently have fairly short-term data. -- Gary M. Ansel, MD, Mid Ohio Cardiology Consultants Columbus, Ohio gansel@mocvc.com

There is no question that drug-eluting stent technology has had a dramatic impact on endovascular therapies for coronary artery occlusive disease. There still, however, remain questions to be answered in regard to optimal patient selection, long-term durability and late thrombosis risk. While drug-eluting technology applied to peripheral arterial occlusive disease has promise, there are vast differences in anatomy and the morphology of occlusive disease in peripheral vascular beds. Currently, non drug-eluting stent technology has worked very well in the aortoiliac segment, with low rates of restenosis. While not all of the mechanisms have been elucidated, it is believed that the larger luminal diameter as well as the arterial architecture appear to result in less proliferative response. The Achilles’ heel for endovascular reconstruction in the periphery is primarily in the infrainguinal segment, in which restenosis rates with bare metal stents have been less than optimal. One of the questions that will need to be answered is whether the drug-eluting stent technologies will reduce the proliferative response and subsequent restenosis in arteries that are subject to significantly greater mechanical stresses than what is seen in the coronary arteries. Typically lesions are long and are in locations in which mechanical torsion and flex play a significant role. Questions remain with regard to stent construction and architecture that can withstand these changes and whether a drug-eluting component will provide significant benefit. The one area where I do believe that drug-eluting stent technology may have a substantial impact is in renal revascularization. While there is some movement, particularly with respiratory excursion, typical renal artery stenoses are short segments that are not subject to the same type of torsional stress that one sees in the superficial femoral artery. To suggest that drug-eluting stent technology represents a panacea for the future I believe is misguided. Careful, comparative studies in a variety of different peripheral vascular beds will be required to determine optimal application of this new and exciting technology. -- J. Michael Bacharach, MD, MPH, North Central Heart Institute, Sioux Falls, SD jhatch@ncheart.com

From its inception, DES technology was appropriately viewed as an exciting, ‘game-changing’ new development that promised to revolutionize endovascular therapy. And we now know that it has had a major impact in coronary revascularization. While not completely ‘conquering’ the restenosis challenge, it has certainly demonstrated to make a huge difference in the rates of hyperpalstic restenosis following coronary stenting. It was inevitable that extrapolation of these concepts and emerging realities would lead to the expectation of similar outcomes in non-coronary arterial beds, especially in such vascular territories as the superficial femoral artery (SFA), where in-stent restenosis constitutes a major failure mode and the most important limitation to the expansion of endovascular interventional strategies for infrainguinal revascularization. Unfortunately, data so far available are less than confirmatory in this regard. It is not clear yet whether the sub-optimal results with DES stenting in the SFA are related to inherent difficulties with the vessel itself, or whether they represent learning-curve challenges with drug dosing and delivery for this particular application, or combinations thereof. In any case, it would seem fair to state today (November 2004) that DES stents are unlikely to become the kind of transformational technology they have come to represent in coronary revascularization. But it is still too early to enunciate ‘final’ impressions, for little if any information is available to judge DES performance in several critical vascular beds, such as the renal and carotid arteries. In the end, industry and leading investigators will do well by not limiting the scope of their research pursuits to DES devices, and by continuing to explore other avenues in the never-ending journey to achieve successful and durable approaches for endovascular recanalization. -- Frank J. Criado, MD, Director, Center for Vascular Intervention Chief, Division of Vascular Surgery Union Memorial Hospital/MedStar Health Baltimore, Maryland; frank.criado@medstar.net

I am not as optimistic that a drug-eluting stent (DES) will have as major of an impact in on percutaneous peripheral interventions (PPI) as in PCI, at least not in the near future, because of the multiple, basic differences in the nature of PVD vs. coronary artery disease. It is likely that the restenosis mechanism and failure modes in PPI are very different than in PCI. Recent renal artery stenosis (RAS) data has shown that in-stent restenosis (ISR) is probably a continuous problem and not just an acute phenomenon (the initial 6–8 weeks) as in PCI, meaning we simply do not know as much about ISR in PPI as in PCI. This raises the question of an entirely different set of ISR mechanisms than just intimal hyperplasia. The SIROCCO data seems to confirm the RAS experience, with a 40% SFA nitinol stent ISR rate at 24 months. SIROCCO also identified nitinol stent fractures, which raises further questions about our current stent platforms in treating PVD. We have a long way to go to understand the failure modes or ISR in PPI. I am, though, optimistic and very excited now that finally clinicians and industry are investing their time and resources into understanding the huge impact of PVD, and are now willing to put forth efforts to seek ways to improve PPI care and outcomes. We must remember that we have over two decades invested in PCI research, but only a fraction of that time and those resources have been allotted to developing PPI. I am confident that the emerging realities in PPI treatment will improve outcomes, which will require new and improved stent and non-stent treatment platforms, and probably a combination of both. I strongly believe that multiple modes of pharmaceutical assistance will be necessary in treating PVD and creative pharmacology assistance methods will be developed to treat the PPI patient both locally and systemically. I believe the reality today, however, is that it is just not as simple to transfer our current knowledge and treatments from PCI to PPI. Over the next decade, though, we will identify a “DES-equivalent” treatment that will make a major impact on PPI restenosis. -- David E. Allie, MD, Director of Cardiothoracic and Endovascular Surgery Director of Peripheral Vascular Studies Cardiovascular Institute of the South/Lafayette Lafayette, Louisiana; david.allie@cardio.com

Although drug-eluting stents have had a major impact on coronary intervention, their usefulness in non-coronary interventions is less clear. The temptation to extrapolate based on success in the coronaries — results that suggest drug-eluting stents may actually produce outcomes similar to those with coronary bypass — is considerable. Unfortunately though, drug-eluting stents have not yet had a demonstrable effect on reducing restenosis after non-coronary interventions. Indeed, follow-up in the SIROCCO trial has shown fractures in nitinol stents and higher-than-expected rates of late restenosis in such interventions. Stent fracture has also been a complication following femoral application, so the usefulness of these devices in peripheral intervention also remains uncertain. Nevertheless, we are hopeful that drug-eluting stents may benefit patients with femoropopliteal and infrapopliteal lesions, which are notoriously difficult to treat. Current stent designs do not address the potential for thrombosis in this vascular region though, and, ultimately, lesions in patients with severe resting claudication, ulcers, or who require limb salvage may be best treated using biodegradable devices, which are not yet available. Given that restenosis is uncommon in aortic, carotid, subclavian, and vertebral stenting, the utility of drug-eluting stents may be somewhat limited. Perhaps the most promising frontier for drug-eluting stents is as a treatment for renal artery stenosis. In patients with stenoses at the ostium, specially designed devices might be very useful. Unlike the femoral area, this vascular region is fairly protected and the potential for stent fracture is likely to be lower. The use of drug-eluting stents in non-coronary vessels has not yet been as successful as we hoped. The early results indicate it will be important to focus on ways to improve stent strength and durability while retaining characteristics that preserve ease of delivery. At present, it appears that additional research, particularly in the renal and femoral arteries, may be warranted. -- Richard Heuser, MD, Phoenix Heart Center at Saint Joseph’s Hospital and Medical Center;  richardheuser@phoenixheartcenter.com