Translation Pathway for Coronary Stent Development
Unmet Clinical Needs
Stephen Ellis, MD
Chuck Simonton, MD
Gregg W. Stone, MD
Originally envisioned as a mean to “prop up” dissections and prevent abrupt vessel closure engendered by the trauma of balloon angioplasty, coronary stents have evolved not just to serve this purpose but to also become the most common means of coronary revascularization worldwide due to their relatively predictable and safe reduction of coronary stenosis, and their less invasive nature (1).
That said, drug-eluting stent (DES) outcomes certainly could be improved upon and if this were to happen, indications for their use might well broaden.
Short term limitations include: general requirement to place a ≥2 mm vascular access device; need for anticoagulation to prevent stent thrombosis (2-4); anatomy poorly suited for stents (5% to 15%); and occasional difficulty in delivery (5% to 15%).
Longer-term limitations include: risk of restenosis due to accumulation of neointimal tissue; sometimes precipitated by strut fracture (5) (5% to 15% in the first year [6,7] and 1% to2% per year thereafter ), late development of neoatherosclerosis (9) leading to recurrent angina and/or myocardial infarction (1% to2% per year beginning around year 2 ) and the occasional prevention of bypass surgery due to stent blockage of the intended anastomosis site (1%). The numeric estimates are based upon data and insights from “real-world” populations, not selected patients enrolled in randomized trials.
Taking the long view that these devices are typically implanted in patients expected to live 15 to 25 years (unpublished Cleveland Clinic interventional database), data find average survival after discharge post-stenting to be about 17 years.
Although not directly related to the stents, patient outcomes are significantly affected by progression of atherosclerosis in arterial segments not stented. Control of atherosclerosis by medical means is a primary objective in patients who receive stents.
Specific Unmet Clinical Needs
Better Long-Term Outcomes Beyond 1 Year: Current devices are associated with an approximately 2% per year adverse event rate beyond 1 year after implantation. The device itself serves as “an irritant,” due to inflammation from its polymer, restriction of normal vasomotion (changes smooth muscle cell phenotype from contractile to proliferative), and other forms of trauma (e.g., strut fracture.) Recognition of this problem has led to the development of bioresorbable stents or scaffolds intended to eventually remove “the irritant,” but these devices have had their limitations. Polymer-free drug-eluting devices have also been developed, thus removing the inflammation-engendering aspect of most current DES. Still, looking at the totality of patient experience, this problem is associated with the highest rate of overall major adverse consequences.
Reduced Restenosis Over First 4-12 Months: Restenosis still occurs not uncommonly when stents are required to treat long lesions, smaller diameter vessels, patients with diabetes, and patients with bypass grafts in particular (4). Perhaps stronger or combination antiproliferative drugs, or more homogeneous drug application on stents might mitigate this problem
Less or Shorter-duration DAPT: The optimal duration of dual antiplatelet therapy (DAPT) is patient dependent and continues to be debated. Nonetheless, at present, no DES requires less than 3 months of DAPT. This leads to an increased risk of bleeding and sometimes precludes stent use in patients requiring other forms of anticoagulation (e.g., warfarin or direct oral anticoagulants in some patients with atrial fibrillation). Stents that hasten endothelial healing and minimize inflammation might lessen the need for DAPT.
Improved Ease of Delivery through Small-caliber Systems: Despite tremendous advances in device diameter and flexibility, stents are occasionally difficult to deliver and require ancillary equipment (e.g., mother-in-child devices) to do so. The consistent ability to use <6-F systems would also facilitate a predominantly radial access approach and same-day outpatient percutaneous coronary intervention for many patients.
Better Stents for Bifurcation Lesions: The apparent need for large device diameter and the heterogeneity of bifurcation lesions have hampered the development and uptake of bifurcation-specific stents (10). Nonetheless, the current “piecemeal” approach to bifurcation stenting is both time-consuming and leads to suboptimal results (11). Better stents for this problem are needed.
Fracture-free Stents: Depending on how it is assessed, stent fracture may have been seen in 3% to 15% of stents and is consistently been seen to be associated with a two to four times increased risk of device thrombosis and restenosis (12). More fracture-resistant stents, presuming structural changes don’t lead to other problems, would improve long-term outcomes.
Other Unmet Needs
Other unmet needs to be considered would include disease-specific devices (e.g., diabetes), less allergenic devices (nickel is the most common allergen), and much more flexible covered stents (to treat iatrogenic coronary perforations).
Cardiovascular disease remains the most common cause of death worldwide in the 21st century (13). Development of new stents meeting all or most of these needs would be expected to further improve patient mortality, morbidity, and quality of life by improving outcomes associated with demonstrable stenosis, as well as even perhaps preventing adverse events associated with identified “vulnerable plaque” (14).
- Iqbal J, Gunn J, Serruys PW. Coronary stents: Historical development, current status and future directions. Brit Med Bull. 2013;106:193-211.
- Palmerini T, Biondi-Zoccai G, Della Riva D, Mariani A, Genereux P, Branzi A, Stone GW. Stent thrombosis with drug-eluting stents: Is the paradigm shifting? J Am Coll Cardiol. 2013;62:1915-21.
- Montalescot G, Brieger D, Dalby AJ, Park SJ, Mehran R. Duration of dual antiplatelet therapy after coronary stenting: A review of the evidence. J Am Coll Cardiol. 2015;66:832-47.
- Cassese S, Byrne RA, Tada T, et al. Incidence and predictors of restenosis after coronary stenting in 10 004 patients with surveillance angiography. Heart. 2014;100:153-9.
- Lee MS, Jurewitz D, Aragon J, Forrester J, Makkar RR, Kar S. Stent fracture associated with drug-eluting stents: Clinical characteristics and implications. Catheter Cardiovasc Interv. 2007;69:387-94.
- von Birgelen C, Basalus MW, Tandjung K, et al. A randomized controlled trial in second-generation zotarolimus-eluting resolute stents versus everolimus-eluting xience v stents in real-world patients: The twente trial. J Am Coll Cardiol. 2012;59:1350-61.
- Kereiakes DJ, Meredith IT, Windecker S, et al. Efficacy and safety of a novel bioabsorbable polymer-coated, everolimus-eluting coronary stent: The evolve ii randomized trial. Circ Cardiovasc Interv. 2015;8.
- Galloe AM, Kelbaek H, Thuesen L, et al. 10-year clinical outcome after randomization to treatment by sirolimus- or paclitaxel-eluting coronary stents. J Am Coll Cardiol. 2017;69:616-24.
- Park SJ, Kang SJ, Virmani R, Nakano M, Ueda Y. In-stent neoatherosclerosis: A final common pathway of late stent failure. J Am Coll Cardiol. 2012;59:2051-7.
- Latib A, Colombo A, Sangiorgi GM. Bifurcation stenting: Current strategies and new devices. Heart. 2009;95:495-504.
- Lee JM, Park KW, Koo BK, Kim HS. Stenting of coronary bifurcation lesions: A literature and technical review. Curr Cardiol Rep. 2015;17:45.
- Kan J, Ge Z, Zhang JJ, et al. Incidence and clinical outcomes of stent fractures on the basis of 6,555 patients and 16,482 drug-eluting stents from 4 centers. JACC Cardiovasc Interv. 2016;9:1115-23.
- Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the global burden of disease study 2010. Lancet. 2012;380:2095-128.
- Finn AV, Nakano M, Narula J, Kolodgie FD, Virmani R. Concept of vulnerable/unstable plaque. Arterioscler Thromb Vasc Biol. 2010;30:1282-92.