Preventing Recurrent Strokes with Carotid Drug-Eluting PTA for Delayed In-Stent Neointimal Hyperplasia

A 79-year-old man experienced an episode around 10:30 PM while watching TV, when he had difficulty getting up from sitting, felt like he could not lift his legs to get up.  Patient’s wife thought that his speech appeared garbled, and the patient felt concerned that he was having trouble getting words out.  His wife also thought that he appeared to be drooling out of the right side of his mouth.  Denied any facial droop and reports that she was looking for this symptom because she was concerned that he may be having a stroke.  The symptoms resolved after 2 to 3 minutes.  Patient also stated he had a slight headache.  Denied neck pain, chest pain, or shortness of breath.  Patient’s PMH included chronic kidney disease, hypertension, and hyperlipidemia.  On presentation in the ED, he had returned to baseline (normal) with an NIHSS of 0 (1230 AM-630 AM).  No IV tPA was administered.  He was loaded with Plavix 300 mg, admitted for observation for a TIA and an MRI of the Brain was obtained (600 AM), demonstrating small diffusion positive ischemic injury in the left insular cortex (and lack of flow void in the left MCA) (Figure 1 A).

Figure 1.

At approximately 6:30 AM as he was coming out of the MRI, the patient was noted to acutely progress to severely hemiparesis on the right side, with dysarthria, without aphasia or gaze preference (NIHSS 8).  Emergent CTA and CTP were performed per our Stroke Protocols which demonstrate a large territory of tissue at risk in the left Frontal lobe MCA territory (Figure 1 B).  CTA confirmed a complete occlusion of the left ICA at the Common Carotid Artery Bifurcation (Figure 2 A) with a tandem embolic occlusion of the M1 segment of the left MCA (Figure 2 B).

Figure 2.

CT Perfusion reveals a large, mismatched territory of hypoperfusion of prolonged time to perfusion (TMax) and relatively preserved Cerebral Blood Flow <30%, suggesting potentially salvageable penumbral ischemic brain injury (Figure 1 B).  Neuroendovascular Intervention was pursued based on the large vessel occlusions and favorable Cerebral Perfusion profile.  A loading dose of ASA 600 mg PR was administered.  Under MAC Anesthesia, an angiogram was performed confirming 100% occlusion of the left internal carotid artery at its origin with no antegrade opacification of the left intracranial circulation and Tandem distal occlusion of the left MCA M1 segment (Figure 3 A and B).

Figure 3.

We then decided to proceed with emergent angioplasty of this left ICA occlusion in an effort to establish antegrade flow and a pathway for intracranial navigation and thrombectomy.  Utilizing digital roadmap, a Viatrac 4 x 40 PTA balloon was primarily navigated over a Synchro 2 standard microwire across the left ICA stenosis.  After being positioned across the lesion, the balloon was gradually inflated over approximately 30 seconds to 14 atm until waisting of the balloon was observed.  Post angioplasty angiography demonstrates significant improvement in the left ICA occlusion with approximately 60 to 70% residual stenosis however brisk antegrade flow into the left intracranial circulation.  Post stent deployment angiography demonstrates significant improvement in the stenosis now approximately 30-40% residual stenosis (Figure 4 A and B).

Figure 4.

Angiography of the left intracranial ICA circulation confirms persistent occlusion of the proximal left M1 MCA segment.  At this point, the Jet 7/3 max penumbra aspiration system was then reinserted and carefully navigated across the residual high-grade stenosis of the left ICA.  Utilizing digital roadmap, the left MCA M1 segment occlusion was traversed with the microwire, followed by the 3 max aspiration catheter, followed by placement of the Jet 7 aspiration catheter within the thrombus within the proximal left M1 segment. The Jet 7 aspiration catheter was then removed under negative pressure at the guiding catheter/sheath level.  Post thrombectomy angiogram demonstrates complete revascularization of the left MCA representing TICI 3 complete reperfusion with no distal branch occlusions observed (Figure 5 A and B).

Figure 5.

Intracranial angiograms confirmed complete revascularization without any branch occlusions.  Patient remained hemodynamically stable during this emergency procedure without symptomatic bradycardia or hypotension following angioplasty or stenting.  Immediate postoperative neurologic examination demonstrates complete reversal of the right-sided hemiparesis with absence of drift, facial symmetry, fluent speech, language comprehension, visual fields (NIHSS 0).  He made a complete recovery and was cleared for discharge home with home care with no deficits, MRS 0, 2 days after intervention.

Over the next 6 months, he continued to do very well having return to all his activities of daily living with no limitations. He denied any issues with language, vision, lateralizing weakness, speech, swallowing, balance, or gait. Followup MRI, CTA, and catheter angiography were performed at 3 months, demonstrating no significant infarcts (including prior diffusion positive insula-reversed!!!) and further passive expansion of the self-expanding stent with no significant residual stenosis (<10% per NASCET) at the Carotid Stent, and brisk filling the left ICA intracranial circulation (Figure 6 A and B).

Figure 6.

The patient continued to do well and remain asymptomatic without recurrent events and underwent follow-up CTA at 12 months from his initial event and revascularization (Figure 7A).  This study demonstrated severe in-stent restenosis at the left ICA origin secondary to profound neointimal hyperplasia within the proximal-mid thirds of the stent which was confirmed with catheter angiography as high-grade (>80%)(Figure 7 B and C).

Figure 7.

At this point, extensive discussion and consideration of potential therapeutic options were performed, including embolic protection filter, repeat angioplasty, repeat stenting, or angioplasty and/or stenting with drug-eluting devices for compassionate use of treatment of intimal hyperplasia and high-grade recurrent stenosis.  Based on the angiographic anatomy and appearance of the stenosis in the vessels, we decided to proceed with primary percutaneous transluminal angioplasty with a drug-eluting balloon (Figure 8).

Utilizing digital roadmap, a 4 x 40 mm Lutonix 035 drug eluting balloon was carefully advanced over a 0.035 guidewire and was placed across the high-grade stenosis within the left ICA.  The Lutonix™ DCB catheter is a drug-coated balloon catheter that delivers paclitaxel to the arterial wall in a single, short inflation. Paclitaxel is an anti-proliferative drug commonly used to prevent arterial restenosis. The percutaneous angioplasty balloon was then gradually inflated to 4-6 atm where it was maintained for approximately 90 seconds to allow deposition of the drug into the intimal walls of the stenosis/blood vessel.  At this point, the balloon was then gradually inflated to 12 atm to further stretch and angioplasty the vessel over 30-45 seconds after which the balloon was rapidly deflated.  Post angioplasty angiography demonstrates revascularization of the left ICA with no residual stenosis within the angioplastied segment.  There is brisk antegrade flow into the intracranial circulation with returned shift of the watershed to filling of the left ACA and left MCA on the left common carotid injection.  No distal branch occlusions were identified.  No significant bradycardia or hypotension was experienced during PTA (Figure 8 and 9).

Figure 8.

Figure 9.

Discussion:

Our patient presented with a Tandem (ICA + MCA) occlusion, which can be found in as many as 20% of stroke patients.  This sub-type of anterior circulation LVO’s responds very poorly to IV-tPA alone, with only 22.7% improving > 4 pts. and  only 18.2% achieving functional independence at 3 months (mRS<3).[i]  As Neuroendovascular Therapy has gained more widespread acceptance and experience, many Neurointerventionalists commonly employ a combination of Emergent PTA and Stenting in combination with Intracranial Mechanical Thrombectomy for these critically ill patients.   In an early study of 170 patients treated at 4 German Stroke Centers, successful revascularization to TICI 2b or better (>50% reperfusion) was achieved in 77%, in-hospital Mortality of 19%, Favorable mRS < 3 in 36%, and Hemorrhage Transformation in 9% of patients.[ii]  More recent experiences include the Thrombectomy in Tandem Lesion registry (TITAN) have confirmed improved outcomes with Combined Stenting and Thrombectomy with or without tPA with 90d favorable outcomes in 51-62% of their patient cohorts.[iii]

The optimal technical approach and treatment strategies for these scenarios remain controversial.  Which lesion to treat first (intracranial vs. extracranial), angioplasty or stenting (primary approach), and anti-platelet/anti-coagulation regimens to be employed?   Proponents of the extracranial first favor collateral augmentation, while intracranial first favor primary revascularization.  PTA alone proponents favor limiting anti-platelet hemorrhagic risks, while stenting proponents favor definitive treatment and limiting risks of re-occlusion.  A recent systematic review and meta-analysis of 33 studies found no significant difference in good outcomes or safety independent of approach utilized, with approximately 50% of patients having good neurological outcomes in their subgroup analysis.[iv]

After initial emergent revascularization of extracranial and intracranial occlusions is achieved, and patients recover, it becomes critically important to closely monitor patient’s carotid and intracranial vessels for recurrent stenosis or occlusion, especially after Stent placement.  Recently, it has been shown in many clinical trials that carotid artery stenting (CAS) had comparable efficacy compared with CEA for primary and recurrent stroke prevention.  However, the benefits of CAS in preventing the future stroke may be complicated by the development of In-Stent Restenosis (ISR). It has been reported that the incidence and morbidity of ISR during CAS were between 1.8% and 20%, depending on the definition of restenosis used and the duration of follow-up, which are considered to be equivalent to restenosis rates after CEA (with the morbidity of restenosis between 1.8% and 22%).^[v],^[vi],[vii]

ISR may be managed with a variety of treatment strategies, including repeating PTA (non-drug), using cutting PTA balloons, repeat Stenting, or even CEA (with Stent explantation).  In the minority of patients who experience primary ISR, the incidence of secondary ISR remains high with traditional approaches, which has prompted early evaluation of Drug Eluting Balloon (DEB) technology, which has demonstrated very favorable results in PAD (Femoral/Popliteal) and Venous circulations. Theoretically, in contrast to drug-eluting stents (DES), DCBs provide the following potential advantages: (1) short-term, nonpolymeric- based local drug delivery, (2) no permanent metallic scaffold left behind, and (3) enhanced vessel healing due to the relatively short-term permanence of the drug inside the vessel wall. Once paclitaxel is transferred into the vessel wall, it acts by altering cytoskeletons in cells and irreversibly inhibiting arterial smooth muscle cell proliferation.^[viii] Its unique mechanism of action, as well as its highly lipophilic profile, makes this drug ideal for this particular application inhibiting cell proliferation after a single dose use.  Experience using DEB for Carotid re-stenosis are early but promising with many high-volume experienced centers reporting excellent primary and delayed vascular patency and freedom from neurologic symptoms or events.[ix],[x]  Considering the relatively low frequency of symptomatic ISR, a prospectively designed randomized study has not yet been performed, which necessitates the treatment team to use their judgement in selecting treatment strategies for each of their patients.

In conclusion, Tandem occlusions (Extracranial and Intracranial) represent challenging high-risk scenarios with potential for devastatingly poor outcomes.  Combination approaches of mechanical thrombectomy and Carotid PTA and Stent may result in favorable independent outcomes in as many as 1 out of 2 patients if performed early. These patients should be managed cautiously in follow-up in that as many as 3-20% of patients may experience ISR (majority asymptomatic), that may place them at higher risk for Recurrent Stroke.  Many of these patients should be strongly considered for early intervention, especially if presenting with very high grade ISR (>70%) or recurrent symptoms.

References:

[i] Rubiera M, Ribo M, Delgado-Mederos R, et al. Tandem internal carotid artery/middle cerebral artery occlusion: an independent predictor of poor outcome after systemic thrombolysis. Stroke. 2006;37(9):2301-2305. doi:10.1161/01.STR.0000237070.80133.1d

[ii] Behme D, Mpotsaris A, Zeyen P, et al. Emergency Stenting of the Extracranial Internal Carotid Artery in Combination with Anterior Circulation Thrombectomy in Acute Ischemic Stroke: A Retrospective Multicenter Study. AJNR Am J Neuroradiol. 2015;36(12):2340-2345. doi:10.3174/ajnr.A4459

[iii] Anadani M, Spiotta AM, Alawieh A, et al. Emergent Carotid Stenting Plus Thrombectomy After Thrombolysis in Tandem Strokes: Analysis of the TITAN Registry. Stroke. 2019;50(8):2250–2252. doi:10.1161/STROKEAHA.118.024733

[iv] Wilson MP, Murad MH, Krings T, et al. Management of tandem occlusions in acute ischemic stroke – intracranial versus extracranial first and extracranial stenting versus angioplasty alone: a systematic review and meta-analysis. J Neurointerv Surg. 2018;10(8):721-728. doi:10.1136/neurintsurg-2017-013707

[v] de Borst GJ, Ackerstaff RG, de Vries JP, et al. Carotid angioplasty and stenting for postendarterectomy stenosis: long-term follow-up. J Vasc Surg. 2007;45(1):118-123. doi:10.1016/j.jvs.2006.09.013

[vi] Lal BK, Beach KW, Roubin GS, et al. Restenosis after carotid artery stenting and endarterectomy: a secondary analysis of CREST, a randomised controlled trial. Lancet Neurol. 2012;11(9):755-763. doi:10.1016/S1474-4422(12)70159-X

[vii] He, C., Wang, S., Zhou, X., & Yang, Z. (2019). A review on the comparison of different treatments for carotid in-stent restenosis. Canadian Journal of Neurological Sciences, 46(6), 666-681

[viii] Herdeg C, Goehring-Frischholz K, Zuern C, et al. Local catheter-based delivery of antithrombotic or antiproliferative drugs: a new concept for prevention of restenosis. Thromb Res. 2008;123(2):236-243. doi:10.1016/j.thromres.2008.02.015

[ix] Gandini R, Del Giudice C, Da Ros V, et al. Long-term results of drug-eluting balloon angioplasty for treatment of refractory recurrent carotid in-stent restenosis. J Endovasc Ther. 2014;21(5):671-677. doi:10.1583/14-4715MR.1

[x] Bhatia, K., Akhtar, I. N., Akinci, Y., Liaqat, J., Siddiq, F., Gomez, C. R., & Qureshi, A. I. (2020). Drug‐Eluting Balloon Angioplasty for In‐Stent Restenosis Following Carotid Artery Stent Placement. Journal of Neuroimaging, 30(3), 267-275.