This edition of Cutting-Edge Perspectives is headed by Robert Beasley, MD, Mount Sinai Medical Center, New York, New York.
In-stent restenosis (ISR) is frequently encountered in infrainguinal arterial interventions. Several therapies have been approved by the FDA to treat ISR, including the excimer laser (Phillips), the B-Laser (Eximo), drug-coated balloons (DCB), and covered stents. However, restenosis remains high, particularly in total occlusions and long lesions, and a clear decline in patency continues to occur with time. The search for new therapies for femoropopliteal ISR continues. We will be discussing treatment of femoropopliteal ISR with Nicolas W. Shammas, MD, MS. Dr Shammas is an interventional cardiologist and the Founder and President of the Midwest Cardiovascular Research Foundation. He has been treating peripheral arterial disease for 23 years and has been involved in more than 200 national clinical trials. Dr Shammas is the national principal investigator on the Jetstream Atherectomy for the Treatment of In-stent Restenosis (JET-ISR), a prospective multicenter trial evaluating the safety and effectiveness of the Jetstream atherectomy system (Boston Scientific) in treating femoropopliteal ISR.
Robert Beasley, MD: How prevalent is the problem of ISR, and why does it pose a unique treatment challenge?
Nicolas Shammas, MD, MS: Femoropopliteal ISR is very prevalent in patients with nitinol self-expanding bare metal stents (BMS), and the condition is clearly linked with time and lesion length. It is estimated that 20% to 30% of stented patients at 1 year will have restenosis, while up to 49% of stented patients at 2 years will have restenosis. Although restenosis may be reduced with the use of drug-eluting stents (DES) or DCBs, the problem of restenosis progresses over time, and a substantial number of patients will face loss of patency. Treatment of femoropopliteal ISR with percutaneous transluminal angioplasty (PTA) leads to poor results, as patency at 1 year can be as low as 28% to 37%. Chronic total occlusions (CTO) and long lesions have particularly poor outcomes. Recently, the Katsanos meta-analysis identified an association between increased long-term mortality and the use of DES or DCB. In June, the U.S. FDA Circulatory System Devices Panel employed patient-level analysis and reached the same conclusion about long-term mortality. Today, operators need to discuss the pros and cons of paclitaxel-eluting technology with their patients. Patients may or may not elect to pursue this option, even though this technology can significantly reduce ISR and target lesion revascularization. Exploration of other methods of treating femoropopliteal ISR is needed.
Dr Beasley: Is debulking needed in treating
Nicolas Shammas, MD, MS: Debulking is essential in treating femoropopliteal ISR. Restenotic tissue does not respond well to PTA. Even when acute results with PTA look reasonable, there is a rapid loss of patency. In the EXCITE ISR trial, debulking restenotic tissue with the excimer laser showed superior results to PTA at 6 months, which was the primary endpoint. These superior results were also seen at 1 year. The longer the lesion, the wider the gap that was observed between outcomes with the excimer laser vs PTA, with results favoring the excimer laser. Another point to consider is that an ISR CTO is a combination of smooth muscle cell proliferation and thrombus, so debulking with a device that can remove both restenotic tissue and thrombus can be advantageous. However, orbital atherectomy and directional atherectomy are contraindicated in femoropopliteal ISR. Rotational and aspiration atherectomy with Jetstream is off-label in the U.S. but has a CE mark in Europe. Small observational studies have shown that rotational and aspiration atherectomy is effective in debulking ISR, and appears to be safe, but more data are needed.
Dr Beasley: What is your algorithm for treating femoropopliteal ISR?
Nicolas Shammas, MD, MS: The main strategy I use to treat femoropopliteal ISR is debulking followed by DCBs, particularly in longer lesions (>10 cm) and CTOs. I have been involved in the Jetstream ISR and JET ISR studies, which both test Jetstream in femoropopliteal ISR. Jetstream is the main off-label device I use in this setting. For shorter, non-CTO lesions, DCBs alone have been my initial strategy. However, with the paclitaxel and mortality controversy, an informed decision by the patient about paclitaxel and mortality is now part of this algorithm.
Dr Beasley: Can you discuss the JET ISR?
Nicolas Shammas, MD, MS: JET-ISR is an investigator-initiated multicenter, prospective, observational study comparing Jetstream in femoropopliteal ISR with a historic control derived from a meta-analysis of the angioplasty arms of the EXCITE ISR, FAIR, and RELINE trials. The primary endpoint of the study is evaluating target lesion revascularization (TLR) at 6 months in femoropopliteal ISR treated with the
Jetstream device. Patency and TLR at 1 year are secondary endpoints. The study is also evaluating the safety of the Jetstream device in this setting and includes core laboratory evaluation of device-stent interaction. The study completed enrollment of 60 patients with Clinical Events Committee and Data and Safety Monitoring Committee evaluation, and early data may soon be released. JET-ISR was preceded by the JETSTREAM-ISR (29 patients, 32 limbs), a 2-center study that showed no stent-device interaction with the Jetstream based on core laboratory evaluation, as well as a promising TLR and patency rate at 6 months.
Dr Beasley: Is debulking sufficient in treating femoropopliteal ISR? What role could combination therapy play?
Nicolas Shammas, MD, MS: Debulking of femoropopliteal ISR alone is not sufficient to obtain satisfactory long-term results. Jetstream and excimer laser showed a rapid loss of patency beyond the first 6-month follow-up. Freedom from TLR at 1 year was low, in the 50% range. Debulking will likely lead to excellent acute results and less bailout re-stenting, but durable results can only be attained with a biological modifier that inhibits the proliferation of smooth muscle cells. The use of DCBs is important to sustaining good long-term results. In a study by Gandini and colleagues, the combination of laser with DCB was superior to laser alone in treating femoropopliteal ISR. Additionally, in the retrospective JET-SCE study, combination therapy with Jetstream and the Lutonix DCB (BD) yielded excellent long-term freedom from TLR. Again, a discussion with patients regarding the pros and cons of paclitaxel-based therapies should be part of their informed decision.
Dr Beasley: Is distal embolization protection needed in treating femoropopliteal ISR?
Femoropopliteal ISR is a high-risk lesion for distal embolization with atherectomy, laser, or Jetstream. Shorter, non-CTO lesions may have a lower rate of distal embolization. In these lesions, the cost-effectiveness of a filter is questionable. CTOs and long lesions embolize universally with atherectomy, and we routinely use filters in these lesions. However, good technique is important in reducing distal embolization. Slow advancement of the laser or the Jetstream is critical. Even balloon angioplasty in a femoropopliteal ISR CTO can result in embolization, because lesions are typically restenotic-thrombotic. I have a low threshold to use a filter in these patients.
Dr Beasley: Is there a role for drug-eluting stents or covered stents in treating femoropopliteal ISR?
Nicolas Shammas, MD, MS: Drug-eluting stents (Zilver PTX tested mostly in this setting) seem to work well to reduce restenosis in femoropopliteal ISR. However, continued loss of patency is seen over time. Patients will eventually have several layers of stents, and I am not sure that this is the best strategy to treat these patients. Loss of patency over time also occurs with covered stents. In the RELINE trial, the Viabahn stent (Gore) was more effective than PTA in reducing restenosis. However, restenosis continues to be significant in the Viabahn arm, and several stent layers become inevitable in these patients. Re-stenting has not been a favorite strategy of mine. I prefer to debulk and use DCBs under embolic filter protection as needed.
Dr Beasley: What is the role of DCBs in treating ISR?
Nicolas Shammas, MD, MS: In my opinion, DCBs are an integral part of the management of femoropopliteal ISR. I believe that DCBs, along with debulking, are the best strategy, particularly in treatment of complex ISR CTOs and long lesions. However, we need large, randomized trials to support this strategy, which in my experience, has yielded overall excellent results. Additionally, information about paclitaxel and increased mortality risk needs to be part of the discussion of a DCB strategy with patients.
Disclosure: Dr Beasley reports that he is a consultant or an advisory board member for BD, Boston Scientific, Cook Medical, CSI, Medtronic, Philips/Spectranetics, and Terumo. Dr Beasley can be contacted at email@example.com
Disclosure: Dr Nicolas Shammas receives educational and research grants from Intact Vascular, Phillips, Boston Scientific, VentureMed Group and Bard. Dr Shammas can be contacted at firstname.lastname@example.org