DES “Club Sandwich”: A Viable (If Imperfect) Option for Recalcitrant Restenosis

Since the advent of percutaneous transluminal coronary angioplasty (PTCA) in the late 1970s, the long-term efficacy of catheter-based coronary revascularization has been challenged in a significant proportion of patients by the occurrence of recurrent stenosis at the site of treated de novo lesions. The incidence of balloon restenosis decreased substantially with the shift away from standalone PTCA to the elective use of bare metal stents (BMS) in the 1990s, largely through reduction in elastic recoil and negative remodeling of the vessel thus preserving the acute luminal gain associated with balloon dilatation.^1,2 Early enthusiasm for routine stenting was tempered however with the observation that perhaps as much as 15–40% of stented patients experienced late loss of lumen within the first 6 months post-procedure via in-stent restenosis (ISR), the end result of excessive neointimal proliferation at the site of stent implantation.³ The next major advance in the reduction of first-time restenosis came with the wide adoption of drug-eluting stents in the first half of the last decade. Pooled estimates of the early first-generation drug-eluting stent (DES) trials found that sirolimus- and paclitaxel-eluting stents yielded an estimated 3 to 4-fold reduction in ISR as compared with BMS.⁴ All the while however, investigator and clinician alike have been forced to acknowledge that first-time ISR has been reduced but certainly not eliminated. The past decade of aggregate experience has confirmed that ISR represents a persistent problem with greater associated morbidity than initially thought and a far higher degree of recurrence than seen with treatment of de novo disease.^5,6 In the years predating the advent of DES, BMS ISR was addressed with some combination of balloon dilatation, rotational atherectomy, repeat BMS implantation and vascular brachytherapy with reported rates of success varying greatly. The introduction of DES offered a straightforward and more efficacious solution to the BMS ISR problem by way of implantation of a second layer of metal, commonly referred to as a “stent sandwich”.^7–10 Recurrent ISR post-DES placement for BMS ISR continues to occur however and represents an even more challenging clinical subset with fewer validated therapies still. In this issue of the Journal of Invasive Cardiology, Meliga and colleagues offer insight into one possible solution.¹¹ To extend the colloquialism, patients receiving a three-layer (“club”) stent sandwich, are studied.

In this report from the Stent-in-Stent Cube (SIS³) Registry, a total of 40 patients presenting to 3 participating tertiary care Italian medical centers over a 5-year period with recurrent, symptomatic restenosis of a DES placed for BMS ISR, were identified and retrospectively analyzed for a 2 year follow-up period. Specific choices relating to procedural technique, equipment, adjunctive pharmacotherapy, use of intravascular imaging, DES choice and duration of antiplatelet therapy were made on the basis of operator preference and local practice standards. There was no use of rotational atherectomy reported and the majority (33/40 patients, 82.5%) underwent a “switch” strategy wherein they received a DES other than the restenosed second DES and the remainder a strategy to continue with implantation of a DES similar to the one they already had. High pressure DES deployment and post-dilatation was performed in the majority of patients as was aggressive sizing of post-dilatation balloon relative to artery. At mean follow-up of nearly 2 years and with no patients lost to follow-up, survival was noted to be 100% and survival free of ischemic endpoints, 82%. Target lesion revascularization was 12.5% and target vessel revascularization, 17.5%. Definite or probable stent thrombosis (by the Academic Research Consortium definitions) only occurred in 1 patient (2.5%). The key findings per the authors, were that second-time DES for recurrent ISR was associated with excellent technical success, survival and event-free survival. It was also noted that a “switch” strategy offered a numerically better TLR rate as compared with re-implantation of the same DES type.

In considering the therapeutic options for ISR, one must first acknowledge the various, often overlapping mechanisms which result in the clinical entity and attempt to assess the relative contribution of each. The restenotic process has primarily been ascribed to exaggerated neointimal proliferation, a process which incorporates vascular inflammation, smooth muscle cell migration and extracellular matrix synthesis.^12,13 Antiproliferative agents such as -limus analogues and paclitaxel favorably modulate this process but numerous specific technical and biologic factors may impact efficacy in the individual patient. Unequal drug delivery and elution may result from trauma to the stent or polymer during advancement of the device as well as from variability in drug distribution through the diseased intima contacting abluminal stent struts.¹⁴ Inadequate stent coverage of balloon-injured segments of vessel or uncovered edge dissections have been proposed as possible mechanisms for focal edge- and articulation gap restenosis.¹⁵ As mentioned, resistance to systemically administered agents inhibiting mammalian target of rapamycin (mTOR) has been reported in the oncologic literature and therefore may also potentially contribute to clinical DES failure although this remains unproven at present.¹⁶ Various mechanical factors may also present clinically as ISR: Whereas conventional wisdom suggests that elastic recoil has been eliminated by stenting, lack of necessary radial force in high-recoil segments such as aorto-ostial locations and in left main coronary arteries, may yet play a role.¹⁷ Under-sizing and/or under-expansion of DES have similarly been shown to be other important, if under-recognized technical considerations contributing to both first-time as well as recurrent DES ISR.¹⁸

The SIS³ Registry investigators have demonstrated in broad strokes that repeat DES implantation in the setting of initial failure of DES after BMS ISR merits strong consideration with the observed TLR and TVR rates for a third layer of metal falling within the ranges reported by others for a second layer of metal, but well above rates reported for the first layer of DES placed for de novo native vessel disease.¹⁹ Although the total number of patients in this study was small, this could also be taken as a signal that the incidence of repeat ISR is falling in the current DES era. Importantly, both paclitaxel- and sirolimus-eluting stent failures were studied and use of both devices comparably distributed as both the second and third stents implanted. The very limited use of everolimus-eluting stents is incongruous with practice at many U.S. centers today, however. The reported distribution of DES ISR characteristics is in agreement with other published data, with the majority of patients presenting with focal or multifocal ISR and therefore expected to have more favorable revascularization outcomes than those with diffuse/proliferative ISR or total occlusion, independent of procedural strategy.²⁰ One notable limitation is the very low use of intravascular ultrasound in the present analysis, rendering it impossible to assess the primary mechanism of ISR and by extension, the primary mechanism of benefit post-PCI. This becomes an important albeit subtle point when more aggressive balloon sizing and inflation/deployment pressures were used in the vast majority of patients. One could speculate that in the setting of focal ISR resulting from stent under-expansion, intravascular imaging and aggressive balloon dilatation without re-stenting could also yield acceptable results. Finally, the signal of benefit with a DES “switching” strategy adds to the body of intriguing and conflicting data outlined by the authors. While the science underlying optimal DES selection in this scenario may be complex, the actual choice in clinical practice is often a very simple and intuitive one with many operators understandably gravitating to a different DES platform than the one which has failed.

In conclusion, second-time DES implantation for recurrent ISR currently represents the most straightforward “finishing step” in a therapeutic approach which may also include intravascular imaging, lesion preparation with high-pressure balloon dilatation, cutting- or scoring-balloon angioplasty or rotational atherectomy. Cilostazol, a selective PDE3 phosphodiesterase inhibitor has demonstrated value in reduction of first-time ISR of both BMS and DES and is sometimes administered after PCI for recurrent ISR in an empiric but as yet untested capacity.^21,22 Recognizing the multitude of variables which may contribute to clinical DES failure, the specific approach undertaken must necessarily be customized for individual patient- and lesion-specific considerations. Given the shift away from use of first-generation DES in the U.S. in favor of cobalt-alloy everolimus- and zotarolimus-eluting stents, the optimal approach for ISR of these devices should ideally also be studied. Finally, investigational technologies such as drug-eluting balloons and bioabsorbable stents offer tantalizing potential advantages over currently available options. Given that nearly 1 in 5 patients in this cohort ultimately failed their third PCI attempt and the enormous global burden of restenosis, the search for better therapies is critical. If proven efficacious in ongoing clinical investigations, these and other novel therapies may serve as additional refinements to the ever-evolving treatment paradigm for recalcitrant restenosis.

References

1. Nobuyoshi M, Kimura T, Nosaka H, et al. Restenosis after successful percutaneous transluminal coronary angioplasty: serial angiographic follow-up of 229 patients. J Am Coll Cardiol 1988:12:616-623.
2. Serruys PW, Luijten HE, Beatt, KJ, et al. Incidence of restenosis after successful coronary angioplasty: A time-related phenomenon. A quantitative angiographic study in 342 consecutive patients at 1,2,3 and 4 months. Circulation 1988;77:361-371.
3. Brophy JM, Belisle P, Joseph L, et al. Evidence for use of coronary stents: A hierarchical Bayesian meta-analysis. Ann Intern Med 2003;138:777-786.
4. Babapulle MN, Joseph L, Bélisle P, et al. A hierarchical Bayesian meta-analysis of randomised clinical trials of drug-eluting stents. Lancet 2004;364:583-591.
5. Chen MS, John JM, Chew DP, et al. Bare metal stent restenosis is not a benign clinical entity. Am Heart J 2006;151:1260-1264.
6. Moustapha A, Assali AR, Sdringola S, et al. Percutaneous and surgical interventions for in-stent restenosis: Long-term outcomes and effect of diabetes mellitus. J Am Coll Cardiol 2001;37:1877–1882.
7. Kastrati A, Mehilli J, von Beckerath N, et al. Sirolimus-eluting stent or paclitaxel-eluting stent vs balloon angioplasty for prevention of recurrences in patients with coronary in-stent restenosis: A randomized controlled trial. JAMA 2005;293:165-171.
8. Holmes DR Jr, Teirstein P, Satler L, et al. Sirolimus-eluting stents vs vascular brachytherapy for in-stent restenosis within bare-metal stents: The SISR randomized trial. JAMA 2006;295:1264-1273.
9. Stone GW, Ellis SG, O’Shaughnessy CD, et al. Paclitaxel-eluting stents vs. vascular brachytherapy for in-stent restenosis within bare metal stents: The TAXUS V ISR randomized trial. JAMA 2006;295:1253-1263.
10. Alfonso F, Perez-Vizcayno MJ, Hernandez R, et al. A randomized comparison of sirolimus-eluting stent with balloon angioplasty in patients with in-stent restenosis: Results of the Restenosis Intrastent: Balloon angioplasty versus elective Sirolimus-eluting stenting (RIBS-II) trial. J Am Coll Cardiol 2006;47:2152-2160.
11. Meliga E, De Benedictis M, Gagnor A, et al. New drug-eluting stent implantation for recalcitrant in-stent restenosis treated with drug-eluting stents. The Stent-in-Stent Cube (SIS3) Registry. J Invasive Cardiol 2011;23:365–368.
12. Curfman GD. Sirolimus-eluting coronary stents. N Engl J Med 2002;346:1770-1771.
13. Marks AR. Sirolimus for the prevention of in-stent restenosis in a coronary artery. N Engl J Med 2003;349:1307-1309.
14. Rogers C, Tseng DY, Squire JC, et al. Balloon-artery interactions during stent placement: A finite element analysis approach to pressure, compliance, and stent design as contributors to vascular injury. Circulation Research 1999;84:378-383.
15. Lemos A, Saia F, Ligthart JM, et al. Coronary restenosis after sirolimus-eluting stent implantation: Morphological description and mechanistic analysis from a consecutive series of cases. Circulation 2003;108:248-249.
16. Kurmasheva RT, Huang S, Houghton PJ. Predicted mechanisms of resistance to mTOR inhibitors. Br J Cancer 2006;95:955–960.
17. Battikh K, Rihani R, Lemahieu JM. Acute stent recoil in the left main coronary artery treated with additional stenting. J Invasive Cardiol 2003;15(1):39-42.

18. Fujii K, Mintz GS, Kobayashi Y, et al. Contribution of stent underexpansion to recurrence after sirolimus-eluting stent implantation for in-stent restenosis. Circulation 2004;109:1085-1088. 
19. Mehilli J, Byrne RA, Tiroch K, et al for the ISAR-DESIRE 2 Investigators. Randomized trial of paclitaxel- versus sirolimus-eluting stents for treatment of coronary restenosis in sirolimus-eluting stents. The ISAR-DESIRE 2 (Intracoronary Stenting and Angiographic Results: Drug Eluting Stents for In-Stent Restenosis 2) Study. J Am Coll Cardiol 2010;55:2710–2716.
20. Corbett SJ, Cosgrave J, Melzi G, et al. Patterns of restenosis after drug-eluting stent implantation: Insights from a contemporary and comparative analysis of sirolimus- and paclitaxel-eluting stents. Eur Heart J 2006;27:2330–2337.
21. Weintraub WS. The pathophysiology and burden of restenosis. Am J Card 2007;100 (5)Suppl 1:S3-9. 
22. Lee SW, Park SW, Kim YH, et al. A randomized, double-blind, multicenter comparison study of triple antiplatelet therapy with dual antiplatelet therapy to reduce restenosis after drug-eluting stent implantation in long coronary lesions: Results from the DECLARE-LONG II (Drug-Eluting Stenting Followed by Cilostazol Treatment Reduces Late Restenosis in Patients with Long Coronary Lesions) trial. J Am Coll Cardiol 2011;57:1264-1270.

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From University of Chicago Medical Center, Chicago, Illinois.
Disclosure: The author has completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Nathan reports honoraria and consulting fees from Medtronic, Inc.
Address for correspondence: Sandeep Nathan, MD, MSc, FACC, FSCAI, Assistant Professor
of Medicine, Interventional Cardiology Staff, University of Chicago Medical Center, 5841 South Maryland Avenue, MC 5076, Section of Cardiology, Chicago, IL 60637-1470. Email: snathan@medicine.bsd.uchicago.edu