New devices for the treatment of atherosclerotic vascular disease: A view from pathology

Drug-eluting stents have revolutionized percutaneous interventional procedures for the treatment of coronary atherosclerotic disease by a dramatic reduction in restenosis. However, late stent thrombosis has emerged as a safety concern in patients with complex disease.

Masataka Nakano

Renu Virmani

Our autopsy studies of patients receiving drug-eluting stent (DES) implants have revealed delayed arterial healing, characterized by uncovered stent struts and absence of endothelialization, as the primary substrate for late stent thrombosis. In addition, excessive inflammatory reaction to polymers has been documented not only at autopsy, but also in clinical studies, and some have suggested that new technologies such as fully biodegradable stent or drug-eluting balloons (DEBs) may be safer than DES for drug delivery. Moreover, restenosis, although seen uncommonly, still occurs primarily in the presence of severe vessel injury, uneven stent expansion, or stent fracture.

We have also recently described the presence of accelerated neo-atherosclerosis as another mechanism of late stent thrombosis in DES. Self-expanding DES with sirolimus-group drugs have also been utilized, especially in peripheral artery disease, resulting in only limited success, whereas the paclitaxel-coated nitinol stent has shown early success in PAD. Some of these findings have been identified in preclinical animal models, which help demonstrate biological responses of devices to predict acute and long-term safety and efficacy in man.

Biodegradable scaffold

The biodegradable drug-eluting scaffold (stent) is a novel approach that provides short- and mid-term vessel support combined with drug-delivery capability without the long-term limitations of current DES. In preclinical models, percent luminal stenosis and inflammation decrease gradually over time, and no persistent inflammation is identified after full degradation of the scaffold; the vessel returns to almost normal physiology with complete endothelialization and compact contractile smooth muscle cells, indicating the elimination of the risk for thrombosis, restenosis or neo-atherosclerotic change.

Although these findings appear promising, there are issues yet to be resolved, such as the size and integrity of the scaffold, and its behavior in highly calcified arteries. Also, scaffold thickness, although similar to the first generation of DES, may cause severe vessel injury during implantation, inducing intense inflammation and subsequent greater neointimal overgrowth. Moreover, struts can be more easily collapsed and deformed by overexpansion, especially in calcified arteries; this will lead to non-uniform circumferential strut distribution affecting local drug concentration. Serruys and colleagues have reported promising results in stable noncalcified lesions in two clinical studies; however, the behavior in complex or calcified lesions will have to be determined.

Drug-eluting balloons

Instead of local drug delivery via polymers on stent struts, drug-elution from the balloon surface has been reported to be an effective mechanism of delivering drug directly to the vessel wall at high enough concentration while maintaining low systemic exposure. One of the theoretical advantages of DEBs over DES is the potential for even and uniform drug deliverability to the diseased vessel wall, as well as better healing. For optimal drug release kinetics, carriers and/or solvents are utilized to achieve sufficient drug retention, although this has not been validated comprehensively. For DEBs to have long-term success, significant drug retention must be demonstrated beyond 28 days in animal models. In histopathologic studies in non-atherosclerotic animal models, DEBs rarely demonstrate circumferential uniform drug effect on the intima-media, as well as longitudinally, thus raising the issue of efficacy in man.

It is also worth emphasizing that no polymer or metal struts are permanently implanted in the vessel wall with a DEB, and therefore, DEBs offer superiority because the risk for delayed arterial healing is dramatically reduced. Nevertheless, acute recoil remains an intrinsic drawback of DEB, as no radial force is there to maintain the vessel widely open once the balloon is deflated. It is therefore likely that the best application of DEB treatment would be for in-stent restenosis, or possibly as an adjunct therapy for bare metal stent usage, as has been demonstrated in several clinical trials. Although DEBs have been approved in Europe after small clinical studies published in prominent journals, none to date have received approval by the FDA. Today, the best formulation remains unknown, as no head-to-head comparisons between DEBs have been made in clinical or preclinical studies.

Self-expanding DES

The idea of self-expanding stents has existed since the introduction of bare metal stents but was discarded because early self-expanding stents had excessive neointimal growth that was presumably attributed to continuous injury and inability to place the stent accurately (geographic miss). Self-expanding stents made of nitinol are thought to be effective in preventing stent fracture due to their elasticity, deformability and flexibility, which are favored for the treatment of carotid and lower extremity usage, allowing greater mobility. However, several clinical trials of self-expanding bare metal stent showed restenosis rates of more than 15%. Alternatively, it has been suggested that self-expanding DES may work even better than balloon-expandable DES. Our experience in preclinical model with self-expanding DES showed minimal wall injury and a continuous increase in stent area, along with decrease in percent luminal stenosis over time.

The clinical outcomes, however, were unfavorable for self-expanding DES in peripheral arteries with a high incidence of restenosis. The reasons of this unfavorable outcome remain unknown but presumably related to the waning of drug effects with excessive inflammation triggered by continued expansion after implantation. Other issues may include the choice of drug. Most of these studies utilized the sirolimus group of drugs, but a recent study using paclitaxel directly on self-expanding DES in PAD for above-the-knee lesions was successful in reducing neointima. Large randomized studies are needed to confirm these results.

Limitations to overcome

Obviously, we need to make continuous efforts to develop new devices to overcome the shortcomings of current devices because preclinical and clinical studies have elucidated continued problems and needs for improvement as summarized in the Table. Limited research budgets are an obstacle to appropriate investigations needed to improve understanding.

Also, the hurdles for approval are greater as the FDA requirements become stricter, needing huge budgets that squeeze the small- to mid-sized companies and decrease innovation.

Renu Virmani, MD, is president and medical director of the CVPath Institute Inc., in Gaithersburg, Md., and is a member of the Cardiology Today Editorial Board.

Masataka Nakano, MD, is a cardiovascular fellow at the CVPath Institute.

For more information:

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Disclosure: Drs. Nakano and Virmani report no relevant financial disclosures.