Are drug-coated balloons and drug-eluting stents the future in intracranial atherosclerotic disease?

Alternative treatment options for patients with intracranial atherosclerotic disease (ICAD) are needed, given its prevalence worldwide and the associated risk of recurrent ischaemic events. Here, Philipp Gruber and Professor Luca Remonda (Department of Neuroradiology at Cantonal Hospital Aarau, Aarau, Switzerland) look at previous studies to evaluate the viability of using drug-coated balloons (DCB) and drug-eluting stents (DES) in the treatment of intracranial atherosclerotic disease, and how they will play an increasingly important role in the not too distant future.

Intracranial atherosclerotic disease (ICAD) is responsible for 8–10% of strokes worldwide, its prevalence varies across populations, ranging from 10% in Caucasian up to about 40% in Asian populations. First-line therapy of symptomatic ICAD, in particular anti-platelet monotherapy, remains the best medical treatment. However, despite aggressive medical treatment, the annual risk of recurrent ischaemic events is still high with up to 18% in patients with >70% intracranial stenosis.¹ In particular, patients with high-grade stenosis (70-99%), patients with haemodynamically relevant stenosis—as shown in the natural history study GESICA²—and patients with unstable atherosclerotic plaque have an increased risk of stroke recurrence. Therefore, alternative treatment modalities are needed.

Endovascular treatment (EVT) for symptomatic ICAD treatment has been long debated since the first description of percutaneous transluminal angioplasty in a symptomatic basilar ICAD by Sundt et al in 1980.³ Since the negative SAMMPRIS and VISSIT trials,⁴ endovascular treatment of symptomatic ICAD—especially percutaneous transluminal angioplasty stenting—has been reluctantly used. Nevertheless, recent results from the WAEVE trial demonstrated a significantly lower periprocedural stroke and death rate of 2.9%,⁵ which encourages consideration of EVT for symptomatic intracranial atherosclerotic disease.

Besides immediate periprocedural complications such as local dissection, subarachnoid haemorrhage or perforator ischaemia, EVT of intracranial atherosclerotic disease also carries the middle- to long-term issue of restenosis. The restenosis rate for both PTA as well as transluminal angioplasty stenting has been reported to be high. Both transluminal angioplasty stenting and percutaneous transluminal angioplasty lead to vascular wall injuries that induce a complex biological cascade of inflammatory responses and wound healing processes. These processes promote the proliferation of smooth muscle cells leading to neo-intimal hyperplasia. It has been recognised that neo-intimal hyperplasia is mainly responsible for restenosis.

To overcome this major limitation of stenting and percutaneous transluminal angioplasty, various anti-proliferative and immuno-modulatory drugs have been evaluated to prevent neo-intimate hyperplasia. Today, two different drug families are most commonly used: the limus drug family, consisting of mammalian target of rapamycin (mTOR) inhibitors (e.g. sirolimus) and calcineurin inhibitors (e.g. Tacrolimus), which are used in drug-eluting stents, and paclitaxel, a highly lipophilic anti-proliferative agent that is a microtubule stabiliser that inhibits mitosis, which is commonly used in DCB’s. Anti-proliferative drugs are integrated into a carrier matrix attached to either a balloon or stent platform. After deploying the DES or while inflating the DCB, the drug can be administered locally at the lesion site.

Both DCB and DES have been very successfully used in interventional cardiology for more than a decade. Numerous studies have proven their efficacy and safety for cardiac atherosclerotic patients. In the neurovascular field, several case series and a few studies have shown that this technique in patients with the primary symptomatic ICAD is feasible, safe and might be effective, while no data were available for DCB until 2018.

DCB offers several advantages over DES. Using DCB, no residual foreign body, nor radial force wall stress is left after the intervention. This has a positive impact on local flow dynamic as well as feared late adverse material-tissue reaction. Furthermore, DCB allows homogeneous anti-proliferative drug coverage of the whole stenosis surface in contrast to DES, by which only 15% of the plaque surface can be coated with anti-proliferative drugs. DCB are more flexible compared to DES offering access to reach more lesions, especially in the tortuous neurovascular anatomy of ICAD patients. A shorter duration of recommended dual anti-platelet therapy (DAPT) might be possible for DCB since there is a lower risk of delayed endothelialisation and therefore lower late or very-late thrombosis compared to DES as shown in cardiac patients. Of course there are drawbacks of percutaneous transluminal angioplasty alone in comparison to stenting, such as immediate recoil phenomenon or higher residual stenosis degrees that might have an impact on restenosis.

Recently, two case series and one study have reported positive results on preliminary experience with DCB use in symptomatic ICAD. Our retrospective single-center cohort study of 19 symptomatic ICAD patients compared Neuro Elutax SV (Aachen Resonance, Germany)—a DCB specifically designed for neurovascular use—with the Gateway/ Wingspan stent system (Boston Scientific, USA).^6,7 We showed that the use of this specific DCB was feasible and safe. In addition, we found that this DCB treatment was superior to the DES regarding asymptomatic and symptomatic recurrence over a median follow-up of nine and a half months. Very recently, Chinese group reported on their preliminary DCB experience of 30 symptomatic ICAD patients using SeQuent Please (b.braun, Germany) with a mean follow-up of nearly ten months—a DCB originally designed for cardiac use.⁸ Their results support our findings regarding feasibility and safety and there was only one asymptomatic restenosis. At the same time, another case series of 10 symptomatic ICAD patients treated at our institution with SeQuent Please NEO—the latest generation of SeQuent Please, offering higher flexibility and better pushability—demonstrated convincing results regarding feasibility and safety, as well as good short-outcomes.⁹

Presently, DCB offer several advantages over DES as outlined above. But, several issues have to be addressed. A clear concept for patient selection should be established, and it has to be discussed which deployment technique should be performed, such as the submaximal angioplasty technique as we have used in our studies. Despite all the technical advances during the past decade, the devices have to be optimised and closely adapted to the neurovascular requirements. Finally, large randomised trials should be carried out to increase the power and reliability of data.

In conclusion, alternative treatment options for ICAD patients are needed since ICAD has a high prevalence worldwide and even with the best medical treatment the risk of recurrent ischaemic events is high. DCB is a feasible and so far safe endovascular technique for ICAD patients. Therefore, the DCB technique has the potential to play an important role in symptomatic ICAD treatment in the near future.

Figure 1: Illustrative Case of DCB use in a symptomatic ICAD patient

A patient with an ischaemic event in the posterior middle cerebral artery territory due to a symptomatic high-grade stenosis of the terminal internal carotid artery segment  carotid artery stenosis on the same side.

1. Pre-interventional reformatted 3D-convantional angiogram showed a eccentric high-grade terminal internal carotid artery stenosis (80%).
2. SeQuent Please NEO (2.0mm x10mm) was successfully deployed over the lesion (red circle) and submaximally inflated with 8 bar.
3. Post-interventional control angiogram revealed a residual stenosis (50%).

Philipp Gruber and Professor Luca Remonda are affiliated with the Department of Neuroradiology at Cantonal Hospital Aarau, Aarau, Switzerland.

References

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2. Mazighi M, Tanasescu R, Ducrocq X, Vicaut E, Bracard S, Houdart E, Woimant F: Prospective study of symptomatic atherothrombotic intracranial stenoses: the GESICA study. Neurology 2006, 66(8):1187-1191.
3. Sundt TM, Jr., Smith HC, Campbell JK, Vlietstra RE, Cucchiara RF, Stanson AW: Transluminal angioplasty for basilar artery stenosis. Mayo Clin Proc 1980, 55(11):673-680.
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5. WAEVE trial, presentation at International Stroke Conference 2018
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9. Gruber P, Braun C, Kahles T, Hlavica M, Anon J, Diepers M, Nedeltchev K, Berberat J, Remonda L: Percutaneous transluminal angioplasty using the novel drug-coated balloon catheter SeQuent Please NEO for the treatment of symptomatic intracranial severe stenosis: feasibility and safety study. J Neurointerv Surg 2018.