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Drug-eluting devices in supra-aortic lesions

Endovascular treatment of stenotic lesions of supra-aortic vessels is widely accepted valid alternative to thromboendarterectomy both for the anterior and the posterior circulation

Roberto Gandini
Associate Professor of Diagnostic and Interventional Radiology
Jacopo Scaggiante
Resident in Diagnostic and Interventional Radiology 
Enrico Pampana
Consultant interventional radiologist
University of Rome, ‘Tor Vergata’, Italy
Endovascular treatment of stenotic lesions of supra-aortic vessels is a widely accepted treatment both for the anterior and the posterior circulation.
Despite the fact that many approaches have been considered to manage this problem, before the last decade no one has proven to inhibit the neointimal hyperplasia related with the stress generated by percutaneous transluminal angioplasty (PTA) and stents.
However, on the basis of excellent results of drug-eluting devices in the treatment of coronary and peripheral arteries lesions, recent trials with drug-eluting balloons are showing promising results in the management of in-stent restenosis (ISR), with a lower rate of recurrence and retreatment also for carotid arteries disease, although larger randomised studies are necessary.
Currently, companies are introducing new mesh-covered stents to reduce even more potentially harmful plaque debris, thrombus displacement and restenosis rates with good results in the short-term, but no data are available on long-term outcomes. 
With regard to the vertebrobasilar trunk, the outlook is still uncertain, but the use of balloon-expandable drug-eluting stents (DES) seems to be even more recommended than bare-metal stents and surgery, with less periprocedural neurologic adverse events, rate of restenosis and mortality.
With regard to carotid arteries, carotid artery stenting (CAS) is a valid alternative to carotid endarterectomy.
Unfortunately, ISR still represents a potential complication occurring in the self-expandable stents, ranging from 4% for atherosclerotic lesions up to 14% post-thromboendarterectomy (TEA) stenting.1,2
The placement of a stent results in mechanical trauma to artery walls and induces a localised inflammatory response, which in turn triggers a neointimal proliferation and tissue growth.3
Moreover, if ISR is angiographically defined as the presence of  >50% diameter stenosis within a stent, different definitions are often considered on duplex imaging during follow-up in the literature, and consequently reported incidences range widely (from 3–20%). It must be considered that stent placement in this particular area presents challenges due to dynamic stresses, motion of the artery and potential embolic risks.
Because of the lack of well-defined guidelines, many approaches to manage these recurrences have been tried in the past: medical treatment, restenting, and repeated balloon angioplasty (often with cutting balloon).
Unfortunately no one procedure has proved definitive, and neointimal hyperplasia still remains a difficult problem to solve only with the use of simple balloon angioplasty and stenting of carotid arteries.
Thus, in the last decade, on the basis of positive results in terms of clinical outcomes in coronary and peripheral artery lesions using drug-coated balloons (DCB) and drug-eluting stents (DES), some authors have attempted to verify their efficacies in supra-aortic vessels. 
These devices essentially function via the passive transfer of drug into the vessel wall by means of a carrier that helps drug transportation.
Formulations and coating characteristics are strictly responsible of different pharmacokinetic properties, currently under evaluation. 
DCBs with good flexibility and pushability are easier to be delivered to the lesion than stents, although efficacy is dependent on the amount of drug transferred at time of balloon inflation and its retention and distribution because a certain quantity is lost in the bloodstream. By contrast, DES contain the medication inside a polymer in order to release a precisely titrated amount over time.
Fig. 1: A 74-year-old woman previously treated with carotid endarterectomy and carotid stenting presented with a recurrent refractory ISR treated with multiple re-interventions. (A) Ultrasound Doppler control showing an 80% in-stent restenosis. (B) Pre-procedural CT angiography in curved, (C) axial, and (D) volume rendering formats showing the significant in-stent restenosis. (E) The pre-procedural angiogram confirmed the significant in-stent restenosis. (F) Drug-eluting balloon angioplasty was performed with good angiographic results (G). (H) Ultrasound Doppler control shows no significant stenosis at 24 months with no need for retreatment. Before using DEB, the patient developed significant stenosis after only three months from each treatment.
Literature analysis
In our analysis, obtained via a literature search of the PubMed database, studies were included if DCBs and/or DES stenting were performed in the same setting and the clinical course and/or in-stent restenosis rate was evaluated during follow-up. Studies of at least three patients of any age and sex with symptomatic or asymptomatic disease were eligible. 
The variables extracted from each article included the following: indication for stenting, technical success (<30% residual stenosis), types of stent used, periprocedural transient ischaemic attack (TIA)/stroke rate, number of patients and stent types in follow-up imaging, definition and rate of restenosis during follow-up, and rate of symptomatic restenosis during follow-up.
Follow-up was considered evaluable when at least the clinical course or one reliable imaging method, for example, duplex sonography, computed tomographic angiography (CTA), magnetic resonance angiography (MRA), and/or angiography were available.
The validity of the included studies was assessed by examination of a number of features: descriptions of the selection of the population, study size and valid declaration of clinical course and/or information concerning in-stent restenosis during follow-up.
As described by Chakhtoura et al.,4 the first and second generation of DES were related to compression, bending, torsion and fracture, increasing the intermittent triplanar stresses and reducing the artery’s natural movement. Furthermore the risk of restenosis was also increased by deployment of a second stent because of the narrowed carotid lumen. For these reasons, this approach should be discouraged in ISR.
Our analyses yielded three articles regarding paclitaxel-coated balloons and anterior circulation.
Currently, there is no self-expandable DES specifically designed for carotid arteries. This is a potential limit to even better results because meeting the patients’ anatomy could improve coating stability and drug transfer efficiency.
In 2007, our group first used the only monorail DCB on the market at that time (DIOR), produced for treatment of coronary arteries lesions, in a selected group of nine patients with recurrent refractory carotid ISR and multiple endovascular treatments (3.4 ± 0.9 interventions).1 Despite the limited maximum diameter of 4.2mm and the restricted indications for the procedure to maintain a 1:1 DEB size/vessel diameter ratio (ICA diameter <4mm and a type II ISR), this balloon was effective in preventing ISR recurrence in six patients and postponing retreatment for the remaining ones from four months to 18, 25 and 32 months, respectively.
Conversely, in 2009 Montorsi et al.5 and Liistro et al.6 evaluated the efficacy of DCBs in de novo carotid ISR in seven and three patients, respectively, previously treated with CAS using an over-the-wire, 0.035-inch, paclitaxel-eluting balloon (In.Pact Admiral and Amphirion In.Pact).  
With an intravascular ultrasound (IVUS) evaluation, the first group documented an increased minimal lumen and a decreased restenosis area. In addition, at 6 and 12 months, peak systolic velocities after DEB treatment were significantly lower compared with those assessed at comparable intervals after CAS.
The second group reports that at 12, 22, and 36 months, respectively, the patients were still asymptomatic, with duplex-documented stent patency at 6, 12, and 24 months, respectively.
Currently, companies are introducing new mesh-covered stents to further reduce potentially harmful plaque debris, thrombus displacements and restenosis rates.
A recent study7 in a small group of seven patients evaluated the effectiveness and safety of the micromesh Roadsaver Carotid Artery Stent in the treatment of atherosclerotic carotid artery stenosis and tandem lesions in ischaemic stroke patients, showing good results. The device structure is made of a nitinol double layer micromesh to avoid protrusion of plaque through the scaffold.
Moreover, it is worth mentioning the results of two clinical trials using the CGuard™ Embolic Prevention System (EPS), respectively on 30 and 50 patients: CARENET8 and PARADIGM.9
Both have shown positive results in preventing periprocedural and late embolisation by trapping potential emboli against the arterial wall through a MicroNet mesh with pores of only 150–180μm. Evidence reported at EuroPCR 2015 shows the device’s applicability for use in an all-comer population with no major adverse cardiac or neurological events (MACNE) during the procedure and at 30 days, with a procedure success rate of 100%. 
This technology could even represent a step forward in the short-term period, especially compared with published historical control groups of non-mesh covered carotid stents, because the number of new ischaemic lesions was reduced by almost 50% and the average lesion volume per patient was 10 times smaller, as assessed by diffusion weighted magnetic resonance imaging (DW-MRI) after carotid artery stenting.  
These new mesh-covered stents could potentially reduce the restenosis rate but no data are available on long-term outcomes.
With regard to the posterior circulation, the outlook is still uncertain but PTA and stenting of the vertebral artery represent a valid solution to surgery with less periprocedural neurologic adverse events and mortality.10
Two meta-analyses were published recently. Langwieser et al.11 documented that the use of DES for extracranial vertebral artery stenting compared with bare metal stents (BMS) significantly reduces the overall rate of restenosis from 23.7% to 8.2% and recurrence of symptoms from 11.6% to 4.7%, although with a meta-analyses of non-randomised comparative studies.
Tank and colleagues12 reported a significantly lower rate of restenosis, recurrent symptoms, and target vessel recanalisation (TVR).
Thus, these results are currently changing the state-of-the-art. 
DEBs for carotid arteries show promising results in the management of ISR, with a lower rate of recurrence and retreatment, despite larger randomised studies being necessary.
Moreover, the new generation mesh-covered stents are showing promising results in the short-term, while waiting for long-term outcomes. Regarding the vertebrobasilar trunk, the use of balloon-expandable DES seems to be recommended.
  1. Gandini R et al. Long-term results of drug-eluting balloon angioplasty for treatment of refractory recurrent carotid in-stent restenosis. J Endovasc Ther 2014;21:671–7.
  2. Del Giudice C et al. Drug-coated balloon angioplasty to improve carotid stenting outcomes after postendarterectomy restenosis: Fad or an answer to the problem of recurrent restenosis? J Endovasc Ther 2015;22(2):217–9.
  3. Kornowski R et al. In-stent restenosis: contributions of inflammatory responses and arterial injury to neointimal hyperplasia. J Am Coll Cardiol 1998;31(1):224–30. 
  4. Chakhtoura EY et al. In-stent restenosis after carotid angioplasty stenting: incidence and management. J Vasc Surg 2001;33:220–6.
  5. Montorsi P et al. Drug eluting balloon for treatment of in-stent restenosis after carotid artery stenting: preliminary report. J Endovasc Ther 2012;19:734–42.
  6. Liistro F et al. Drug-eluting balloon angioplasty for carotid in-stent restenosis. J Endovasc Ther 2012;19:729–33.
  7. Hopf-Jensen S et al. Initial clinical experience with the micromesh roadsaver carotid artery stent for the treatment of patients with symptomatic carotid artery disease. J Endovasc Ther 2015;22(2):220–5.
  8. Schofer J et al. A prospective, multicenter study of a novel mesh-covered carotid stent: The CGuard CARENET Trial (Carotid Embolic Protection Using MicroNet). JACC Cardiovasc Interv 2015;8(9):1229–34.
  9. Anon. Novel PARADIGM in carotid revascularisation. Last accessed April 2016.
  10. Antoniou GA et al. Percutaneous transluminal angioplasty and stenting in patients with proximal vertebral artery stenosis. J Vasc Surg 2012;55(4):1167–77. 
  11. Langwieser N et al. Baremetal vs. drug-eluting stents for extracranial vertebral artery disease:a meta-analysis of non-randomized comparative studies. J Endovasc Ther 2014;21(5):683–92. 
  12. Tank VH et al. Drug eluting stents versus bare metal stents for the treatment of extracranial vertebral artery disease: a meta-analysis. J Neurointerv Surg 2015. pii: neurintsurg-2015-011697. doi: 10.1136/neurintsurg-2015-011697. [Epub ahead of print] Review. PubMed PMID: 26180094.