In Vivo Study Suggests DES Polymer-Drug Coatings Not Inherently Thrombogenic

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Drug and polymer coatings do not intrinsically raise the risk of stent thrombosis but instead may actually lower it, according to an ex vivo analysis of stent design published online March 21, 2011, ahead of print in Circulation. Other factors such as strut thickness and stent positioning relative to the vessel wall appear to exert greater influence on thrombogenicity.

Researchers led by Kumaran Kolandaivelu, MD, PhD, of the Harvard-MIT Division of Health Sciences and Technology (Cambridge, MA) sought to understand whether DES coatings are any more inherently thrombogenic than other aspects of stent design and deployment. To answer this question, they created an ex vivo flow model using porcine blood and evaluated a range of commercially available and custom-built stents.

In their model, drug/polymer coatings had a beneficial effect, uniformly reducing thrombogenicity relative to comparable BMS. Compared with thin-strutted stents (81 μm), those with thick struts (162 μm) were more thrombogenic; these results were confirmed in vivo using pig models, which demonstrated greater thrombus coverage 3 days after implantation. Malapposed and overlapping stents also had negative effects in the flow model (table 1).

Table 1. Effect of Stent Design and Deployment on Thrombogenicity

“Stent thrombosis is catastrophic, and it is feared that the addition of polymer coatings and drugs increases thrombotic risk,” Dr. Kolandaivelu and colleagues write. “We show here in a controlled model of early [stent thrombosis] that clinically relevant polymer-coated stents are consistently less, not more, thrombogenic than matched bare metal platforms, especially in high-risk interventions. More important to [stent thrombosis] in our models were the interaction of strut dimension and position relative to the vessel wall and the potential alterations in flow and recirculation imposed by the implanted device.”

In fact, thrombogenicity appears to be affected by “synergistic interactions between strut geometry and the local flow environment,” they add.

In an e-mail communication, Dr. Kolandaivelu said that the fact that drug/polymer-coated devices performed better than their bare-metal counterparts was somewhat but not entirely unexpected, given that the model captured acute conditions.

“Most surprising was that subtle design changes such as stent dimension or coating remained important when devices were placed in relevant real-world geometries as exemplified by malapposition or overlap,” he commented. “In fact, the importance of stent design was amplified. Some design features allowed devices to be relatively insensitive to variable deployment while other features made the devices exquisitely sensitive in a manner that was highly related to the local flow patterns. Flow disruptions could vary in size and position relative to the vessel wall, the stent struts, or both. The thrombotic impact of these shifting flow disruptions was dependent on the relative wall and stent reactivities, thus revealing an inherent richness underlying the phenomenon.”

Bench vs. Bedside

Juan F. Granada, MD, of The Jack H. Skirball Center for Cardiovascular Research (Orangeburg, NY), responded to the study with some words of caution. “I think the paper has a lot of merit, because it’s elegantly performed,” he told TCTMD in a telephone interview. “But it’s difficult to translate the [in vitro] results into what we see in the clinical arena.”

The paper acknowledges that the models are simplifications, because they account for vascular wall response while remaining unable to mimic biomechanical strut-wall interactions. As such, the findings’ relevance to clinical settings must be carefully weighed, the authors advise.

“[O]ur ex vivo models create an idealized setting that allows careful and controlled investigation of complex, real-world coronary-like environments,” Dr. Kolandaivelu said, adding that the “models are most relevant to early blood-borne responses occurring soon after device placement.”

Dr. Granada agreed with these caveats, noting that “these types of studies neglect the most important components of PCI, which are the presence of a complex atherosclerotic tissue, the potential thrombogenicity associated with it, the interaction with different components contained in human blood, and the periprocedural uncertainties that actually occur when you do high-risk PCI.” In particular, the use of silicon tubing and porcine rather than human blood are significant factors, he said.

Moreover, due to the routine use of contemporary imaging techniques such as intravascular ultrasound and optical coherence tomography in the setting of high risk-PCI, malapposition and improper stent sizing are now uncommon occurrences in clinical practice, Dr. Granada noted. Not only that, but the type of malapposition described in the paper—created intentionally—differs from the late malapposition that develops over time as a consequence of vascular healing and remodeling commonly seen following DES implantation.

Thus, Dr. Granada said the paper overstates its findings by concluding that DES are less thrombogenic than BMS. “The reality is that although very late thrombotic events are rare in drug-eluting stents, [it is even more rare that] we see any of these events following bare-metal stent implantation. Clinically we are not seeing what is described in the paper,” he concluded.

In terms of clinical practice, the most interesting aspect to the paper may be exploration of flow patterns, said Dr. Kolandaivelu.

“Stent design and deployment are intimately linked and a greater appreciation for the complex flows induced can help shed insight on the variability in procedural outcomes beyond basic clinical descriptions such as device ‘malapposition,’” he said, adding that flow tracking may now “offer a way to further optimize stent design and adjuvant antithrombotic therapies to particular individuals and lesions.”

Note: Dr. Granada is a faculty member of the Cardiovascular Research Foundation, which owns and operates TCTMD.

 

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Source:
Kolandaivelu K, Swaminathan R, Gibson WJ, et al. Stent thrombogenicity early in high-risk interventional settings is driven by stent design and deployment and protected by polymer-drug coatings. Circulation. 2011;123:1400-1409.

 

 

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