Unmet Clinical Needs

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 [8]), late development of neoatherosclerosis (9) leading to recurrent angina and/or myocardial infarction (1% to2% per year beginning around year 2 [7]) 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Taking the long view that these devices are typically implanted in patients expected to live 15 to 25 years (unpublished Cleveland Clinic interventional database), data find average survival after discharge post-stenting to be about 17 years.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.

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 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 21^st 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).