Stent thrombogenicity early in high-risk interventional settings is driven by stent design and deployment and protected by polymer-drug coatings

Abstract

Background: Stent thrombosis is a lethal complication of endovascular intervention. Concern has been raised about the inherent risk associated with specific stent designs and drug-eluting coatings, yet clinical and animal support is equivocal.

Methods and results: We examined whether drug-eluting coatings are inherently thrombogenic and if the response to these materials was determined to a greater degree by stent design and deployment with custom-built stents. Drug/polymer coatings uniformly reduce rather than increase thrombogenicity relative to matched bare metal counterparts (0.65-fold; P=0.011). Thick-strutted (162 μm) stents were 1.5-fold more thrombogenic than otherwise identical thin-strutted (81 μm) devices in ex vivo flow loops (P<0.001), commensurate with 1.6-fold greater thrombus coverage 3 days after implantation in porcine coronary arteries (P=0.004). When bare metal stents were deployed in malapposed or overlapping configurations, thrombogenicity increased compared with apposed, length-matched controls (1.58-fold, P=0.001; and 2.32-fold, P<0.001). The thrombogenicity of polymer-coated stents with thin struts was lowest in all configurations and remained insensitive to incomplete deployment. Computational modeling-based predictions of stent-induced flow derangements correlated with spatial distribution of formed clots.

Conclusions: Contrary to popular perception, drug/polymer coatings do not inherently increase acute stent clotting; they reduce thrombosis. However, strut dimensions and positioning relative to the vessel wall are critical factors in modulating stent thrombogenicity. Optimal stent geometries and surfaces, as demonstrated with thin stent struts, help reduce the potential for thrombosis despite complex stent configurations and variability in deployment.

Conflict of interest statement

Conflict of Interest Disclosures

Dr. Edelman reports research support from Abbott Vascular, Boston Scientific and Cordis Corporation. L. Coleman and V. Giddings are employees of and have equity interest in Abbott Vascular. K. L. Nguyen-Ehrenreich is an employee of Abbott Vascular. The remaining authors report no conflicts.

Figures

FIGURE 1

Flow Loop, Reactive Sites, and Stent Configurations. (A) Closed flow loop with a 2.5cm reactive site. Stents are deployed within reactive sites in desired conformations. Following a run, the stented segment is excised and flushed. Adherent clot is assessed visually and through LDH quantification. To determine the malapposition threshold, indigo dye was used to detect stent-wall contact. (B) Proper stent deployment was modeled using apposed configurations. (C) Incomplete stent deployment was modeled using under-deployed configurations. (D) Overlapping stents were compared to length matched controls.

FIGURE 2

Relative ex vivo thrombogenicity between thin BMS (MLV), thick BMS (TSV), and DES (XVS) in apposed configurations.

FIGURE 3

Ex vivo thrombogenicity among BMS and DES of different designs. (A) LDH thrombus quantification and (B) visible clot as observed between pooled DES and BMS designs showing a class effect. (C) LDH quantification in BMS designs grouped according to strut thickness ( 100μm strut).

FIGURE 4

In vivo thrombogenicity of thin (MLV) and thick (TSV) BMS in porcine coronary arteries (n=6 each). (A, B) Radiographs of the excised arteries confirming full expansion of MLV and TSV platforms respectively. (C, D) H&E staining of prepared sections derived from MLV and TSV devices respectively 3 days post-implant. (E) Morphometric analysis of adherent thrombus as assessed through luminal area measurement of MLV and TSV stented sections. (F) Computational models depicting flow alterations surrounding apposed thick (81μm × 162μm) and thin (81μm × 81μm) struts.

FIGURE 5

Ex vivo and computational assessment of malapposition cases. (A) Thrombogenicity of thin BMS (MLV), thick BMS (TSV), and DES (XVS) when deployed at their malapposition threshold (0–60μm displacement) as compared to apposed MLV controls. (B) Clot mass in MLV platforms deployed in mild (0–60μm), intermediate (150–210μm), and severe (350–400μm) malapposed configurations showing a variable response. (C) Single strut 2-D simulations with varying displacements showing stent-wall recirculation zones which first grow in size, shift downstream of the stent, lose stent communication, and then fade away altogether. (D) Computed flow pattern with severe wall displacements (shown at the centerline) depicting re-emergence of strut-associated recirculation. (E) Increased visual clot burden observed with severe stent-wall displacement. Depending on the relative thrombogenicities of the wall and the stent, the shifting strut-wall recirculation patterns may help explain variability in malapposition-associated ST events.

FIGURE 6

Ex vivo and computational assessment of overlap cases. (A) Thrombogenicity of thin BMS (MLV), thick BMS (TSV), and DES (XVS) when deployed in overlapped configurations as compared with single, length-matched MLV controls. (B) 2-D flow simulations over thin (81μm) and thick (162μm) overlapping stents in congruent or non-congruent configurations. Depending on strut alignment, flow disruptions can be augmented in susceptible geometries (as seen by the recirculation zone spanning the overlapped region in congruent, thick cases).