From the Midwest Cardiovascular Research Foundation, Davenport, Iowa.
Disclosure: Supported by the Nicolas and Gail Shammas Research Fund at the Midwest Cardiovascular Research Foundation (MCRF). MCRF has received research grants from ev3 and Foxhollow.
Manuscript submitted December 4, 2008 and accepted January 9, 2009.
Address for correspondence: Nicolas W. Shammas, MS, MD, Cardiovascular Medicine PC, 1236 E. Rusholme, Davenport, IA 52803 E-mail: email@example.com
Peripheral artery disease (PAD) is a global problem, affecting 12–14% of the general population. Its prevalence increases with age. Peripheral percutaneous interventions (PPI) have sharply increased over the past decade to treat symptomatic PAD. PPI is effective in reducing claudication symptoms and in improving limb salvage in patients with critical limb ischemia. However, PPI is limited by a high rate of repeat revascularization, particularly in the infrainguinal vessels, and by significant distal embolization in a certain subset of high-risk patients. We discuss a strategy addressing the triad of mechanical, biological and procedural factors that need to be optimized for immediate and long-term success in patients undergoing PPI. It is our opinion that a successful strategy for optimal outcomes after PPI is to reduce acute recoil and negative remodeling, inhibit smooth muscle cell proliferation and protect the distal tibial vessels while keeping the procedure safe for both operators and patients.
Peripheral arterial disease (PAD) is a widely prevalent problem in the United States.1 A sharp increase in peripheral percutaneous interventions (PPI) over the past decade has been recently reported.2 This is likely to be partly related to the marked improvement in percutaneous procedural techniques allowing the endovascular specialist to tackle complex and difficult lesions. Although the “tool box” to treat symptomatic PAD has expanded, many unanswered questions have surfaced about the relative effectiveness, safety and application of these devices. Unquestionably, evidence-based PPI is currently several years behind percutaneous coronary interventions. There is as yet no clear consensus on the best approach to treat certain lesion subsets to optimize short- and long-term outcomes.
We describe a strategy to treat PAD based on the following three principles (Figure 1):
1. Reducing acute recoil and negative remodeling, and therefore limiting the need for primary or provisional stenting;
2. Suppressing smooth muscle cell proliferation following vascular injury;
3. Protecting the infrapopliteal vessels to preserve distal flow.
Following is a discussion of each of these principles.
Reducing vessel recoil and negative remodeling and improving vessel compliance
There are many advantages to reducing immediate recoil in PPI. Acute recoil and dissection following superficial femoral artery (SFA) balloon angioplasty leads to suboptimal angiographic results requiring provisional stenting in up to 50% of patients.3 Stenting to avoid acute recoil, however, has its limitations. Current stents continue to have a high rate of fractures that have been linked to an increase in restenosis rates.4,5 Restenosis, with or without stent fractures, presents a challenging treatment problem for the interventionalist. Thrombus is typically found within occluded restenotic lesions and carries a high rate of embolization during treatment.6 Also, balloon angioplasty (PTA) of in-stent thrombotic/restenotic lesions often leads to additional stenting because of suboptimal results. In addition, stents may limit future surgical targets for peripheral bypass, preventing a viable revascularization alternative to patients. Furthermore, it is possible that the effectiveness of upcoming new therapeutic modalities, such as drug-eluting stents or local infusion of antiproliferative drugs, may be negatively influenced by preexisting nitinol or stainless steel stents within a vessel. Finally, despite the reported improvement in restenosis with stenting, the rate of restenosis has remained as high as 37% in the stented patients at 1-year follow up,7 highlighting the overall challenge in treating SFA lesions.
Although primary stenting of the SFA has been shown to have a small but statistically significant advantage over PTA in reducing restenosis, its effectiveness was limited by a similar reintervention rate in both groups at 1 year.7 Also, the added symptomatic improvement with stenting above PTA does not appear until after 6 months to 1 year post treatment,7 which could be explained by the later negative remodeling in the PTA group rather than a reduction of smooth muscle cell proliferation by the stent.8 We hypothesize that if acute recoil and negative remodeling can be reduced using non-stenting interventional modalities, the need for stenting could be significantly reduced.
Preliminary data from a randomized trial of PTA versus atherectomy3 have shown that SilverHawk atherectomy (ev3, Inc., Plymouth, Minnesota) reduces recoil and the rate of stenting during PPI. Cryoplasty also might reduce vessel recoil and dissection, and lead to less stenting.9 This hypothesis is currently being tested in the ongoing POLAR randomized trial. Finally, it remains unclear whether changing vessel compliance in severely calcified vessels can lead to a reduction in dissection and stenting rates.
Reducing smooth muscle cell proliferation
Smooth muscle cell (SMC) proliferation remains the Achilles’ heel of peripheral angioplasty. Although this problem has been markedly reduced in the coronary arteries with the advent of drug-eluting stents, this approach has thus far been unsuccessful in PPI.10,11 Stenting reduces recoil and negative remodeling, but is less likely to impact SMC proliferation.8
Multiple clinical predictors of reduced patency in the femoropopliteal vessels have been reported. The patency rate seems also to be worse in patients with limb ischemia and total occlusions,12 and in patients with a reduced number of runoff vessels.13,14 Furthermore, diabetes15 and longer lesion length16,17 are associated with higher restenosis rates.
Optimal strategies to reduce SMC proliferation have been disappointing. Restenosis remains substantially high with stenting alone and further adjunctive therapy is needed for optimal outcome. There are no large randomized trials to determine the effectiveness of cryoplasty or ablative therapy (laser, SilverHawk atherectomy or orbital atherectomy) on SMC proliferation compared to PTA, but lessons from coronary interventions suggest that they are less likely to be more effective in reducing SMC proliferation. Cutting balloons (Boston Scientific Corp., Natick, Massachusetts) have also failed to reduce restenosis in the periphery. In the the REStenosis CUTting Balloon Evaluation Trial (RESCUT),18 a multicenter, randomized, prospective European trial, 428 patients with in-stent restenosis were randomized to cutting balloon versus angioplasty. At 7-month angiographic follow up, the binary restenosis rate was not different between the groups (cutting balloon 29.8%, angioplasty 31.4%; p = 0.82), with a similar pattern of recurrent restenosis.
Endovascular brachytherapy was shown to reduce restenosis in patients with recurrent but not de novo lesions in PPI. In an analysis of patients from the Vienna 2 and 3 trials, patients with recurrent lesions had a significantly lower restenosis rate with brachytherapy (26% versus 71%, respectively; p = 0.004).19,20 Other studies could not show a predictable long-term benefit with brachytherapy in restenotic femoropopliteal lesions. In one study,21 freedom from angiographic restenosis at 1, 2 and 3 years was 70.7%, 63.1% and 47.1% after angioplasty versus 82.7%, 64.3% and 64.3% after brachytherapy and angioplasty (p = 0.16). External beam radiotherapy (EBRT) alone, however, failed to reduce restenosis.22 Randomized trials of combined EBRT and endovascular brachytherapy versus either one alone are not available. Brachytherapy showed poor long-term data in the coronary and has been discontinued by the majority of cardiac angiography laboratories. It is unlikely that adjunctive brachytherapy alone will continue to be explored at this time for prevention of restenosis in PPI.
Cilostazol appears to offer some reduction in restenosis post PPI and might be a useful adjunct therapy to high-risk patients.23,24 However, a high rate of restenosis continues to be seen in the cilostazol group and a more effective therapy is needed at this time. In addition, oral sirolimus25–27 showed conflicting data on restenosis in the coronary arteries and no data is available regarding its effectiveness in PPI. Finally, a paclitaxel-coated angioplasty balloon28 has recently been reported to reduce restenosis in the SFA. In a small multicenter trial, 154 patients with stenosis or occlusion of a femoropopliteal artery were randomized to standard balloon angioplasty (control), paclitaxel-coated balloons and uncoated balloons with paclitaxel dissolved in the contrast medium. At 6 months, the mean late lumen loss was 1.7 ± 1.8 mm in the standard balloon group versus 0.4 ± 1.2 mm (p 0.05). Duplex ultrasound showed restenosis to be 4.7%, 9.0%, 15.6% and 21.9% at 6, 9, 18 and 24 months, respectively, and was not different between the two groups. The TLR rate for the sirolimus group was 6% and for the bare-metal stent group, 13%. There were no significant differences between the sirolimus-eluting and the bare-metal SMART stents in this study, and the bare-metal stent group had an unexpected lower restenosis rate than expected. In the SIROCCO II trial,11 57 patients with chronic limb ischemia and SFA occlusions or stenoses were randomized to the SMART bare-metal nitinol stent versus sirolimus-eluting stent. The binary restenosis rates, with a cutoff of 50% at 6 months, were zero in the sirolimus-eluting stent group and 7.7% in the bare stent group (p = 0.49). At this time, further research is needed to define the optimal dose, timing and duration of drug elution in patients undergoing PPI.
We believe that a strategy of biodegradable DES use that prevents mechanical recoil and negative remodeling and reduces SMC proliferation, with eventual dissolution of the stent, is likely to be an effective solution to reduce SMC proliferation in PPI. An alternative strategy would be to reduce recoil with existing or improved device technologies coupled with local delivery of antiproliferative drugs.
Protecting the distal vascular bed and maintaining patient and operator safety
Multiple devices are currently available to the endovascular specialist to treat obstructive peripheral arterial disease. The list includes, among others, plain-old balloon angioplasty, cutting balloons, scoring balloon catheters, balloon- and self-expanding stents, and atherectomy/ablative devices such as the SilverHawk, Excimer laser (Spectranetics, Inc., Colorado Springs, Colorado) and the Diamondback 360° Orbital Atherectomy System (Cardiovascular Systems, Inc., St. Paul, Minnesota). Distal embolization (DE) has remained a concern in lower-extremity interventions. DE is generally underrecognized in the distal bed, as digital subtraction angiography may not be routinely performed in these patients post intervention. Also, silent DE is likely to be common and its immediate adverse clinical consequences are infrequent, particularly in the lower-risk vascular beds. In addition, the routine use of DE protection requires expensive embolic protection devices that are currently not reimbursed. EPDs are not yet approved for use in the periphery in the United States, therefore hindering their frequent use. Finally, more data are needed to define the appropriate population that would benefit from EPD use.
Several studies have shown that DE is very prevalent in PPI.29–34 It is unclear what constitutes a “clinically important” DE. This has varied among reports. One report determined that the size of the particulate debris was considered clinically significant if it was ≥ 2 mm.29 Others did not report on the debris size, but reported on the actual rate of serious complications that resulted from DE, such as amputation.30,31 DE also appears to prolong procedure time and leads to greater exposure to radiation and contrast dye.35 In addition, data suggest that the number of patent tibial vessels is a predictor of the patency of treated femoropopliteal vessels.13,14 Preserving distal runoffs could therefore be an important goal to optimize the results of proximal outflow treatment.
Although DE occurs 50–100% of the time and has been described with the majority of devices in the periphery, clinically important DE has been reported in 2–17% of patients (Table 1). It appears to be highest in thrombotic lesions, and with the use of mechanical thrombectomy and SilverHawk atherectomy devices.6,30,31,33 Furthermore, patients with total occlusions and long, irregular and calcified lesions in the setting of a single tibial runoff or severe tibial disease might benefit from EPD. Large, multicenter, prospective registries are needed to determine the predictors of clinically significant DE. Observational data at present suggest that embolic filter protection is safe and feasible in PPI.29,32–34
In conclusion, it is our opinion that a successful strategy in PPI targets the immediate mechanical recoil problem seen with balloon angioplasty, reduces negative remodeling, improves vessel compliance, prevents DE and loss of tibial vessels, and limits SMC proliferation. Although stenting might reduce the mechanical problems seen with balloon angioplasty, we believe that a provisional rather than primary stenting strategy remains an acceptable approach in PPI.