Demystifying Stent Fractures: One Step Closer to Decoding the In-Stent Restenosis Conundrum

Despite recent advances in percutaneous techniques, device designs, delivery system profiles, and operator skills, the management of symptomatic infrainguinal arterial occlusive disease remains a challenge. 

Though peripheral arterial disease is a systemic process that typically affects multiple arterial beds, approximately half of all infrainguinal atherosclerotic lesions localize to the femoropopliteal (FP) segment. The FP arteries are muscular distributing conduits that lie relatively superficial in the thigh, connect to highly mobile articulation sites, and are surrounded by the dynamic thigh muscles. These features render the arterial wall subject to unique biomechanic, anatomic, and hemodynamic forces that cause changes to the artery’s geometry during locomotion. Ambulation causes axial elongation and shortening, while musculoskeletal activities (such as turning, twisting, walking, and bending) are associated with radial compression and other (nonradial) cyclic deformities while the rhythmic pulsatile blood flow produces repetitive radial extension. This distinctive biomechanical environment has not been observed in other vascular beds and appears to explain the artery’s predilection to atherosclerotic lesions that are typically diffuse and complex in nature, respond poorly to revascularization techniques (particularly plain old balloon angioplasty, POBA) and tend to recur and require future reintervention.^1,2

The disappointing performance of POBA (50% acute failure rate necessitating bailout stenting and <40% 12-month patency) and stainless steel stents (rigid, susceptible to crush and restenosis) in the femoropopliteal arteries fueled the search for prostheses that provide sufficient radial force while flexibly conform to the artery to accommodate the biomechanical demands of this segment.^3-7 Consequently, an era of utilizing nitinol, an alloy with unique superelastic and thermal memory properties suitable for the infrainguinal bed, began and led to the development of nitinol self-expanded stents. The superiority of primary and provisional nitinol stenting over POBA was evident by they significantly improved patency rates, particularly in intermediate to long lesions.^8,9 Nonetheless, in-stent restensosis (ISR) was soon recognized as a major limitation to the durability of nitinol stents. In-stent restenosis is caused by intimal hyperplasia, which is an exaggerated healing process to arterial wall barotrauma during angioplasty mediated by inflammatory mechanisms and fueled by ongoing interaction between stent struts and the arterial wall.^10,11

Stent fracture (SF) as a clinical phenomenon came to light in 2004 when Allie and Walker published a landmark report documenting high prevalence of SF (65%) and associated ISR.¹² Soon thereafter, additional observations linked SF to adverse outcomes including ISR, stent thrombosis, pseudoaneurysm formation, and distal embolization.^13-16 The SIROCCO trial was the first to prospectively evaluate the rate of stent fractures in first generation nitinol stents. In this trial, stent fractures were common (20%), most appeared within the first year in subjects who received 3 or more stents, and many were adjacent to stent overlap zones. Importantly, the SIROCCO failed to document strong association between SF and ISR.¹⁷ Nonetheless, the SF issue took center stage and had an enormous impact on femoropopliteal stenting trials. In fact, in June 2006 the FDA mandated monitoring for SF as a safety endpoint in all subsequent stent trials. 

While data on the prevalence of SF and their clinical sequel were being collected, newer nitinol stents were being designed. Several modifications were made to the stent architecture (such as struts length, shape and angles, the density and geometry of the microconnectors and markers), stent material composition, and stent finishing (intensive surface polishing to avoid imperfections). The newer generation stents are stronger, yet more adaptable, and produced in lengths of up to 25 cm to avoid overlap. Moreover, revised stent implantation instructions, particularly avoiding stent elongation during deployment, were widely disseminated. These structural and technical improvements paid off and translated into greater primary patency and remarkably fewer stent fractures. Subsequently, the FDA approved several nitinol stents for femoropopliteal indications. Table 1 summarizes the data on FDA-approved nitinol stents, including patency and SF rates. Collecting data on SF continues to be mandatory because SF remains commonly encountered in practice and its clinical impact is often evident. 

In this issue of Vascular Disease Management, Babaev et al report on a real-life series of 97 consecutive patients who underwent implantation of 205 nitinol stents to 105 of their limbs; and presented with symptomatic ISR approximately 15 months after the index procedure. Based on their in-a-limb analysis, the authors report SF in 30% (31/105 limbs). Despite this relatively high prevalence, SF-related ISR (defined as the presence of a SF within 1 cm from the stenotic lesion) was noted in only 3 limbs. Hence, 10% (3/31) of the limbs with fractured stents had ISR within 1 cm from a fracture, and 2.9% (3/105) of all limbs with ISR had a SF within 1 cm from the stenotic lesion. The authors concluded that while stent fractures are common, their relationship to ISR is rather modest. 

Other notable findings of the study include the absence of a strong relationship between the presence of multiple overlapping stents (28% of limbs had 3 or more overlapping stents) and advanced fractures (56% of fractures were type 3, 4, or 5) and the incidence of fracture-associated ISR. Similarly, the presence of multiple fractures (35% of the limbs had ≥2 SF) did not predict ISR in the affected limb. On the other hand, when multivariate analysis was carried out, ongoing smoking was the only factor associated with stent fractures. 

I would like to congratulate Dr. Babaev for his contribution to Vascular Disease Management and for reigniting the discussion about the important topic of SF and their clinical impact on stent patency and reintervention. Our attempts to study this phenomenon as a clinical event have been hindered by the lack of a standardized reporting system for SF diagnosis and their mechanistic contribution to ISR. Published studies used different formulas to calculate SF prevalence. Some divided the total number of fractures seen on radiographs by the total number of patients reviewed (in-a-patient analysis); while others used the total number of limbs (in-a-limb analysis) or the total number of stents as the denominator. If we apply each of these different definitions, the prevalence of SF in this study will be 45% (total 44 SF/97 patients), 30% (31 limbs with SF/105 total limbs) or 21% (44 SF/205 total number of stents). Similarly, the burden of SF on overall ISR can also differ depending on the denominator used: 3% (3/97), 30% (3/30) or 1.5% (3/205). This highlights the need for standardized reporting. 

The issue of defining the association between SF and ISR based solely on the presence of the two pathologies within 1 cm of each other warrants further discussion. Stent fracture can cause stent instability and compromise stent performance against the biomechanical forces affecting the entire femoropopliteal arterial wall. For example, the presence of a complex (type 3, 4, or 5) fracture can significantly change the interaction between the stent struts (on both sides of the fracture) and the arterial wall; eventually promoting intimal hyperplasia and ISR at regions farther than the predefined 1-cm radius. Therefore, the presence of ISR in fractured stents cannot be attributed exclusively to non-fracture-related factors. Likewise, until other conclusive evidence is available, the presence of SF may be counted as a potential contributor to the development of ISR within the contiguous stented segment.

Another challenge with reporting on SF is related to the diagnostic methodology employed. All operators and technologists should be trained to recognize them. In addition to high resolution digital x-ray imaging in 2 different projections separated by at least 45°, at least 50% magnification should be applied when scrutinizing the integrity of peripheral stents. Moreover, adjudication of the radiographic images should be performed by at least 2 blinded interpreters with reasonable experience and interobserver variability. 

In conclusion, newer stent designs, improved operator skill, revised deployment techniques, production of longer stents, and adherence to best medical therapy and intensive risk factor management have all contributed to superior stent patency and lower restenosis rates. We should also remind ourselves that stents will continue to have their indications in the FP system and we, as a community, need to continue our effort to perfect their engineering and minimize their complications, including SF and ISR.  

References

1. Norgren L, Hiatt WR, Dormandy JA, etal. TASC II Workin Group. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg. 2007;45:Suppl S:S5-S67.
2. Conte MS. Critical appraisal of surgical revascularization for critical limb ischemia. J Vasc Surg. 2013;57(Suppl 2):8S-13S. 
3. Johnston KW. Femoral and popliteal arteries: reanalysis of results of balloon angioplasty. Radiology. 1992;183(3):767-771.
4. Gray BH, Sullivan TM, Childs MB, et al. High incidence of restenosis/reocclusion of stents in the percutaneous treatment of long-segment superficial femoral artery disease after suboptimal angioplasty. J Vasc Surg. 1997;25(1):74-83.
5. Rocha-Singh KJ, Jaff MR, Crabtree TR, Bloch DA, Ansel G; VIVA Physicians, Inc. Performance goals and endpoint assessments for clinical trials of femoropopliteal bare nitinol stents in patients with symptomatic peripheral arterial disease. Catheter Cardiovasc Interv. 2007;69(6):910-919.
6. Grimm J, Müller-Hülsbeck S, Jahnke T, Hilbert C, Brossmann J, Heller M. Randomized study to compare PTA alone versus PTA with Palmaz stent placement for femoropopliteal lesions. J Vasc Interv Radiol. 2001;12(8):935-942.
7. Muradin GS, Bosch JL, Stijnen T, Hunink MG. Balloon dilation and stent implantation for treatment of femoropopliteal arterial disease: meta-analysis. Radiology. 2001;221(1):137-145.
8. Laird JR, Katzen BT, Scheinert D, et al. Nitinol stent implantation versus balloon angioplasty for lesions in the superficial femoral artery and proximal popliteal artery: twelve month results the RESILIENT randomized trial. Circ Cardiovasc Interv. 2010;3(3):267-276.
9. Schillinger M, Sabeti S, Loewe C, et al. Balloon angioplasty versus implantation of nitinol stents in the superficial femoral artery. N Engl J Med. 2006;354(18):1879-1888.
10. Kiguchi MM, Marone LK, Chaer RA, et al. Patterns of femoropopliteal recurrence after routine and selective stenting endoluminal therapy. J Vasc Surg. 2013;57(1):37-43. 
11. Tosaka A, Soga Y, Iida O, et al. Classification and clinical impact of restenosis after femoropopliteal stenting. J Am Coll Cardiol. 2012;59:16-23. 
12. Allie D, Hebert C, Walker C. Nitinol stent fractures in the SFA. Endovascular Today. July/August 2004:22-34.
13. Rits J, van Herwaarden JA, Jahrome AK, et al. The incidence of arterial stent fractures with exclusion of coronary, aortic, and non-arterial settings. Eur J Vasc Endovasc Surg. 2008;36(3):339-345. 
14. Iida O, Nanto S, Uematsu M, et al. Influence of stent fracture on the long-term patency in the femoro-popliteal artery: experience of 4 years. J Am Coll Cardiol Intv. 2009;2(7):665-671. 
15. Scheinert D, Scheingert S, Sax J, et al. Prevalence and clinical impact of stent fractures after femoropopliteal stenting. J Am Coll Cardiol. 2005;45(2):312-315.
16. Neil N. Stent fracture in the superficial femoral and proximal popliteal arteries: literature summary and economic impacts. Perspect Vasc Surg Endovasc Ther. 2013;25(1-2):20-27. 
17. Duda SH, Bosiers M, Lammer J, et al. Drug-eluting and bare nitinol stents for the treatment of atherosclerotic lesions in the superficial femoral artery: long-term results from the SIROCCO trial. J Endovasc Ther. 2006;13(6):701-710.
18. Davaine JM, Azema L, Guyomarch B, et al. One-year clinical outcome after primary stenting for trans-atlanticinter-society consensus (TASC) C and D femoropopliteal lesions (the STELLA “stenting long de l’artere femorale superficielle” cohort). Eur J Vasc Endovasc Surg. 2012;44(4):432-441.
19. Bosiers M, Torsello G, Gissler HM, et al. Nitinol stent implantation in long superficial femoral artery lesions: 12-month results of the DURABILITY I study. J Endovasc Ther. 2009;16(3):261-269. 
20. Bosiers M, Deloose K, Callaert J, et al. Results of the Protégé EverFlex 200-mm-long nitinol stent (ev3) in TASC C and D femoropopliteal lesions. J Vasc Surg. 2011;54(4):1042-1050.
21. Matsumura JS, Yamanouchi D, Goldstein JA, et al. The United States StuDy for EvalUating EndovasculaR TreAtments of Lesions in the Superficial Femoral Artery and Proximal Popliteal By usIng the Protégé EverfLex NitInol STent SYstem II (DURABILITY II). J Vasc Surg. 2013;58(1):73-83.e1. 
22. Gray WA, Feiring A, Cioppi M, et al. S.M.A.R.T. self-expanding nitinol stent for the treatment of atherosclerotic lesions in the superficial femoral artery (STROLL): 1-year outcomes. J Vasc Interv Radiol. 2015;26(1):21-28. 
23. Dake MD, Ansel GM, Jaff MR, et al; Zilver PTX Investigators. Paclitaxel-eluting stents show superiority to balloon angioplasty and bare metal stents in femoropopliteal disease: twelve-month Zilver PTX randomized study results. Circ Cardiovasc Interv. 2011;4(5):495-500.
24. Dake MD, Scheinert D, Tepe G, et al; Zilver PTX Single-Arm Study Investigators. Nitinol stents with polymer-free paclitaxel coating for lesions in the superficial femoral and popliteal arteries above the knee: twelve-month safety and effectiveness results from the Zilver PTX single-arm clinical study. J Endovasc Ther. 2011;18(5):613-623. 
25. Bosiers M, Peeters P, Tessarek J, Deloose K, Strickler S; Zilver PTX Single-Arm Study Investigators. The Zilver® PTX® Single Arm Study: 12-month results from the TASC C/D lesion subgroup. J Cardiovasc Surg (Torino). 2013;54(1):115-122.
26. Laird JR, Jain A, Zeller T, et al. Nitinol stent implantation in the superficial femoral artery and proximal popliteal artery: twelve-month results from the COMPLETE SE multicenter trial. J Endovasc Ther. 2014;21(2):202-212.
27. Patrick J, Geraghty PJ, Mewissen MW, Jaff MR, Ansel GM; VIBRANT Investigators. Three-year results of the VIBRANT trial of VIABAHN endoprosthesis vs bare nitinol stent implantation for complex superficial femoral artery occlusive disease. J Vasc Surg. 2013;58(2):386-395.
28. Lammer J, Zeller T, Hausegger KA, et al. Heparin-bonded covered stents versus bare-metal stents for complex femoropopliteal artery lesions: the randomized VIASTAR trial (Viabahn endoprosthesis with PROPATEN bioactive surface [VIA] versus bare nitinol stent in the treatment of long lesions in super cial femoral artery occlusive disease). J Am Coll Cardiol. 2013;62(15):1320-1327.
29. Saxon RR, Chervu A, Jones PA, et al. Heparin-bonded, expanded polytetrafluoroethylene-lined stent graft in the treatment of femoropopliteal artery disease: 1-year results of the VIPER (Viabahn Endoprosthesis with Heparin Bioactive Surface in the Treatment of Superficial Femoral Artery Obstructive Disease) trial. J Vasc Interv Radiol. 2013;24(2);165-173.
30. Scheinert D, Grummt L, Piorkowski M, et al. A novel self-expanding interwoven nitinol stent for complex femoropopliteal lesions: 24-month results of the SUPERA SFA registry. J Endovasc Ther. 2011;18(6):745-752.
31. Werner M, Paetzold A, Banning-Eichenseer U, et al. Treatment of complex atherosclerotic femoropopliteal artery disease with a self-expanding interwoven nitinol stent: midterm results from the Leipzig SUPERA 500 registry. EuroIntervention. 2014;10(7):861-868.
32. Scheinert D, Werner M, Scheinert S, et al. Treatment of complex atherosclerotic popliteal artery disease with a new self-expanding interwoven nitinol stent: 12-month results of the Leipzig SUPERA popliteal artery stent registry. JACC Cardiovasc Interv. 2013;6(1):65-71.
33. Garcia L, Jaff MR, Metzger C, et al; SUPERB Trial Investigators. Wire-interwoven nitinol stent outcome in the superficial femoral and proximal popliteal arteries twelve-month results of the SUPERB trial. Circ Cardiovasc Interv. 2015;8(5).