Surgery Section - Percutaneous Transluminal Angioplasty of Intracranial Atherosclerotic Stenosis With or Without Stenting

IMPORTANT REMINDER

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PLEASE NOTE: Contracts exclude from coverage, among other things, services or procedures that are considered investigational or cosmetic. Providers may bill members for services or procedures that are considered investigational or cosmetic. Providers are encouraged to inform members before rendering such services that the members are likely to be financially responsible for the cost of these services.

Description

It is estimated that intracranial atherosclerosis causes about 8% of all ischemic strokes. Intracranial stenosis may contribute to stroke in two ways: either due to embolism or low flow ischemia in the absence of collateral circulation. Recurrent annual stroke rates are estimated at 4%–12% per year with atherosclerosis of the intracranial anterior circulation, and 2.5%–15% per year with lesions of the posterior (vertebrobasilar) circulation. Medical treatment typically includes either anticoagulant therapy (i.e., warfarin) or antiplatelet therapy (i.e., aspirin).  The WASID trial (Warfarin-Aspirin Symptomatic Intracranial Disease) was a randomized trial that compared the incidence of stroke brain hemorrhage or death among patients randomized to receive either aspirin or warfarin.  The trialists reported that with a mean 1.8 years of follow-up, warfarin provided no benefit over aspirin and was associated with a significantly higher rate of complications.  In addition, if symptoms are attributed to low flow ischemia, agents to increase mean arterial blood pressure and avoidance of orthostatic hypotension may be recommended. However, medical therapy is considered less than optimal. For example, in patients with persistent symptoms despite antithrombotic therapy, the subsequent rate of stroke or death is extremely high, estimated in one study at 45%, with recurrent events occurring within a month of the initial recurrence. Surgical approaches have met with limited success. The widely quoted Extracranial-Intracranial (EC/IC) Bypass study randomized 1,377 patients with symptomatic atherosclerosis of the internal carotid or middle cerebral arteries to medical care or EC/IC bypass. The outcomes in the two groups were similar, suggesting that the EC/IC bypass is ineffective in preventing cerebral ischemia. Due to inaccessibility, surgical options for the posterior circulation are even more limited.

Percutaneous transluminal angioplasty (PTA) has been approached cautiously in the intracranial circulation due to technical difficulties in catheter and stent design and due to the risk of embolism, which may result in devastating complications if it occurs in the posterior fossa or brain stem. However, improvement in catheter trackability, allowing catheterization of tortuous veins, and the increased use of stents has created ongoing interest in exploring PTA as a minimally invasive treatment of this difficult-to-treat population. Most of the published studies of intracranial PTA have focused on the vertebrobasilar circulation.

Currently, two devices have received FDA approval through the humanitarian device exemption (HDE) process.  This form of FDA approval is available for devices used in the treatment or diagnosis of conditions that affect fewer than 4,000 individuals in the United States per year. and the FDA only requires data showing “probable safety and effectiveness.” An approved HDE authorizes marketing of the humanitarian use device (HUD). However, an HUD may only be used after an internal review board (IRB) approval has been obtained for the use of the device for the FDA approved indication. The labeling for an HUD must state that the device is an humanitarian use device and that, although the device is authorized by Federal Law, the effectiveness of the device for the specific indication has not been demonstrated.  The two devices  and their labeled indications are as follows:

• NEUROLINK® System, which is "indicated for the treatment of patients with recurrent intracranial stroke attributable to atherosclerotic disease refractory to medical therapy in intracranial vessels ranging from 2.5 to 4.5 mm in diameter with greater than or equal to 50% stenosis and that are accessible to the stent system." (3)
• Wingspan™ Stent System with Gateway™ PTA Balloon Catheter, which is “indicated for improving cerebral artery lumen diameter in patients with intracranial atherosclerotic disease, refractory to medical therapy, in intracranial vessels with greater than or equal to 50% stenosis that are accessible to the system.” (3)

Policy/Criteria

Note: This policy does not address percutaneous angioplasty and stenting of carotid or other venous vessels, which are addressed in separate policies (see Cross References below).

Percutaneous transluminal angioplasty with or without stenting is considered investigational, including but not limited to the following arteries:

1. Anterior cerebral artery
2. Basilar artery
3. Carotid siphon
4. Internal carotid
5. Middle cerebral artery
6. Ophthalmic artery
7. Posterior cerebral artery
8. Vertebral artery (distal)

Position Summary

The following discussion focuses on the FDA Summary of Safety and Probable Benefit for the two devices that received approval through the Humanitarian Device Exemption Process.

FDA Data

• NEUROLINK® System (2)

The clinical study investigating the NEUROLINK device is known as the SSYLVIA study (Stenting of Symptomatic Atherosclerosis Lesions in the Vertebral or Intracranial Arteries), a prospective, nonrandomized, multicenter, international study.  Patients were eligible for participation in the study  if they were symptomatic (previous stroke or TIA) due to an angiographically demonstrated, discrete stenosis >50%, in an extracranial or intracranial artery.  The primary endpoint was a composite of stroke and death clinical  outcomes at 30 days, which occurred in 6.6% of patients.  The FDA summary notes that in the WASID study of aspirin and warfarin therapy, the rate of fatal or nonfatal stroke was 14.6% and total stroke or death was 22.5% with a follow-up of 15-19 months, suggesting a potentially superior outcome with the NEUROLINK device.  However, the short length of follow-up in the NEUROLINK study prevents meaningful comparisons.  The FDA Summary of Safety and Probable Benefit concludes, “Therefore, it is reasonable to conclude that the probable benefit to health from using the NEUROLINK System for intracranial stenting for recurrent stroke attributable to intracranial atherosclerosis refractory to medical therapy outweighs the risk of illness or injury, taking into account the probable risks and benefits of currently available devices or alternative forms of treatment, when used as indicated in accordance with the directions of use.

• Wingspan Stent System (3)

The Wingspan Stent System consists of a highly flexible, microcatheter delivered self-expanding nitinol stent, which may be suitable for lesions in the distal internal carotid and middle cerebral arteries.  These arteries are difficult to access with a balloon-mounted stent, such as the NEUROLINK system. (4)  The Wingspan was studies in a prospective, multicenter, single arm trial of 45 patients enrolled at 12 international centers.  Patients were considered eligible if they presented with evidence of recurrent stroke, refractory to medical therapy and thought to be secondary to intracranial stenosis of 50% or greater.  The primary safety endpoint was similar to the SSYLVIA study, i.e., a composite of stroke and death clinical outcomes at 30 days, which occurred in 4.5% of patients.  The FDA summary provided a comparison of various outcomes of the NEUROLINK and Wingspan devices as follows:

The FDA offered the following conclusions concerning the Wingspan device and appeared to base its approval, in part, on the favorable comparison to the NEUROLINK device:

“The Wingspan clinical study treated 45 patients with symptomatic atherosclerotic lesions in intracranial arteries who were refractory to medical therapy.  The lesions were predilated and stented.  Clinical follow-up (42 patients) and angiographic follow up (40 patients) were performed at 6 months.  The type and frequency of observed adverse events including stroke are consistent with or lower than similar neurovascular procedures.  Therefore, it is reasonable to  conclude that the probable benefit to health from using the Wingspan Stent System with Gateway PTA Balloon Catheter for treating in transcranial stenosis outweighs the risk of illness or injury when used in accordance with the Instructions for Use and when taking into account the probable risks and benefits of currently available alternative forms of treatment.”

Other Literature

A number of recent studies report results on angioplasty for intracranial artery stenosis, all but one of the publications found were case series without concurrent controls. Coward and colleagues report long term results of 16 patients from the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS) with symptomatic vertebral artery stenoses who were randomized in equal proportions to receive endovascular therapy (balloon angioplasty or stenting) or best medical treatment alone. (8) Endovascular intervention was technically successful in all 8 patients, but 2 patients experienced transient ischemic attack at the time of endovascular treatment. During a mean follow-up period of 4.7 years, no patient in either treatment group experienced a vertebrobasilar territory stroke, but 3 patients in each treatment arm died of myocardial infarction or carotid territory stroke, and 1 endovascular patient had a nonfatal carotid territory stroke. The authors concluded that patients with vertebral artery stenosis were more likely to have carotid territory stroke and myocardial infarction during follow up than have recurrent vertebrobasilar stroke. They noted that the trial failed to show a benefit of endovascular treatment of vertebral artery stenosis. However, the numbers of patients included was small; larger randomized trials are required.

Marks and colleagues reported a series of 120 patients with 124 intracranial stenoses who were treated by primary angioplasty. (9) All patients had neurologic symptoms (stroke or transient ischemic attack) attributable to intracranial stenosis of 50% or greater. Pretreatment stenoses varied from 50% to 95% and post-treatment stenoses from 0% to 90%. There were 3 strokes and 4 deaths (all neurological) within 30 days of the procedure, giving a combined periprocedural stroke and death rate of 5.8%. A total of 116 patients (96.7%) were available for a mean follow-up time of 42.3 months. There were 6 patients who had a stroke in the territory of treatment and 5 additional patients with stroke in other territories. Ten deaths occurred during the follow-up period, none of which were neurological. Including the periprocedural stroke and deaths, the authors noted an annual stroke rate of 3.2% in the territory of treatment and a 4.4% annual rate for all strokes.

Qureshi and colleagues reported on a non-randomized comparison (angioplasty was used preferentially in patients with more technically challenging lesions) of 44 patients who underwent angioplasty with or without stenting for symptomatic intracranial stenosis. (10) At 12 months, there were no statistically significant differences between groups. However, there was no comparative medical group, and the sample size was relatively small. Firoella reported on initial periprocedural experience with the Wingspan stent in a study of 78 patients, average age 64 years. (11) In this study, 81 of 82 lesions were successfully stented and percent stenosis was reduced (from 75% to 27% after stent placement.) There were 5 (6.1%) major periprocedural neurologic complications with 4 patient deaths within 30 days. Long-term outcomes were not reported in this initial report. Zaidat reported on the National Institutes of Health registry on use of the Wingspan stent for symptomatic intracranial stenosis. (12) This article reported on 129 patients from 16 medical centers treated with a Wingspan stent in this registry between November 2005 and October 2006. Patients with symptomatic 70% to 99% intracranial stenosis were enrolled. The technical success rate was 96.7%. The mean pre- and post-stent stenoses were 82% and 20%, respectively. The frequency of any stroke, intracerebral hemorrhage, or death within 30 days or ipsilateral stroke beyond 30 days was 14.0% at 6 months (95% CI = 8.7% to 22.1%). The frequency of 50% or more restenosis on follow-up angiography was 13 of 52 (25%). The authors concluded that the use of a Wingspan stent in patients with severe intracranial stenosis is relatively safe with a moderately high rate of restenosis. They also noted that comparison of the event rates in high-risk patients in warfarin-aspirin symptomatic intracranial disease (WASID) versus this registry does not rule out either that stenting could be associated with a substantial relative risk reduction or has no advantage compared with medical therapy; thus, a randomized trial comparing stenting with medical therapy is needed. In an accompanying editorial, Haley notes that the Zaidat report suggests that intracranial stenting is not a panacea for intracranial atherosclerosis and that the high complication and restenosis rates justify clinical equipoise for a randomized, controlled trial comparing stenting with medical therapy. (13) A number of other studies were identified through the MEDLINE search. None of these were randomized studies. Many were small series with limited follow-up. Thus, given the uncertain impact of this procedure on clinical outcomes, this is considered investigational.

Cochrane Reviews (5, 6)

A 2005 Cochrane review focused on randomized trials of angioplasty of vertebral artery stenosis compared with best medical therapy alone and included review of the SSYLVIA study and a large number of case series.  The review did not include the Wingspan study.  The Cochrane review noted that only one completed randomized trial was available.  This trial, known as the CAVATAS trial (Carotid and Vertebral Artery Transluminal Angioplasty Study), included 504 patients with external carotid artery disease and a small group of 16 patients with symptomatic vertebral artery stenosis.  While there were no strokes or deaths from any causes in the eight randomized to endovascular therapy, this small study was insufficient to permit conclusions.  The authors concluded, “…there is currently insufficient evidence to support the routine use of percutaneous transluminal angioplasty (PTA) and stenting for vertebral artery stenosis.  Endovascular treatment of vertebral artery stenosis should only be performed within the context of randomized controlled trials.”  Additionally the authors noted, “Little is known about the natural history of vertebral artery stenosis and what constitutes best medical treatment.  Future trials should concentrate on comparing different medical treatments such as antiplatelet and anticoagulant drugs as well as comparing endovascular intervention with medical treatment.” (5)

A 2006 Cochrane Review focused on angioplasty for intracranial artery stenosis. The authors indicated that no randomized controlled trials were found. There were 79 articles of interest consisting of case series with three or more cases. The safety profile showed an overall perioperative rate of stroke of 7.9% (95% confidence intervals 5.5% to 10.4%) and perioperative stroke or death of 9.5% (95% CI 7.0% to 12.0%). The authors concluded that at present there is insufficient evidence to recommend angioplasty with or without stent placement in routine practice for the prevention of stroke in patients with intracranial artery stenosis. The descriptive studies show that the procedure is feasible although carries a significant morbidity and mortality risk. Evidence from randomized controlled trials is needed to assess the safety of angioplasty and its effectiveness in preventing recurrent stroke. (6)

Specialty Societies Position Statement (7)

In 2005 The American Society of interventional and Therapeutic Neuroradiology (ASITN), the Society of interventional Radiology (SIR), and the American Society of Neuroradiology (ASNR) jointly published a position paper regarding angioplasty and stenting for cerebral atherosclerosis.  This position statement reviewed a number of case series and also the SSYLVIA and Wingspan studies.  The following statement was offered, although the underlying rationale and process for development for the position statement was not provided:

“The ASITN, SIR, and ASNR concur that sufficient evidence now exists to recommend that intracranial angioplasty with or without stenting should be offered to symptomatic patients with intracranial stenoses who have failed medical therapy.  Endovascular interventions are intensive services provided to patients who are at very high risk for stroke and typically have multiple comorbidities.  Similar to revascularization for extracranial carotid artery stenosis, patient benefit from revascularization for symptomatic intracranial arterial stenosis is critically dependent on a low per procedural stroke and death rate and should thus be performed by experienced neurointerventionists.  We recommend reimbursement by third party insurers so that these patients may have access to such interventions.  Continued attempts to improve the benefits of endovascular therapy are warranted.”

Summary

In summary, the literature continues to be dominated by case series, registry data, and non-randomized prospective trials performed in support of FDA approval through the humanitarian device exemption process.  From an evidence basis, as noted by the Cochrane reviews and in contrast to the position statement by the three relevant specialty societies, these studies are inadequate to permit scientific conclusions.

References

1. BlueCross BlueShield Association Medical Policy Reference Manual, Policy No. 2.01.54
2. FDA Web site: www.fda.gov/cdrh/pdf/H010004b.pdf (Verified 08/20/08)
3. FDA Web site:  www.fda.gov/cdrh/ode/H050001sum.html  (Verified 08/20/08)
4. Hartmann M, Bose A, Berez S et al.  Wingspan stent in intracranial atherosclerotic disease.  Neuroradiology  2004;46:S80
5. Coward LJ, Featherstone RL, Brown MM.  Percutaneous transluminal angioplasty and stenting for vertebral artery stenosis.  Cochrane Database Sys Rev  2005;2:CD000516
6. Cruz-Flores S, Diamond AL. Angioplasty for intracranial artery stenosis. Cochrane Database Syst Rev 2006; 3:CD004133
7. Higashida RT, Meyers PM, Connors JJ et al.  Intracranial angioplasty and stenting for cerebral atherosclerosis: a position statement of the American Society of Interventional and Therapeutic Neuroradiology, Society of Interventional Radiology and the American Society of Neuroradiology.  AJNR Am J Neuroradiol  2005;26(9):2323-7
8. Coward LJ, McCabe DJ, Ederle J et al. Long-term outcome after angioplasty and stenting for symptomatic vertebral artery stenosis compared with medical treatment in the carotid and vertebral artery transluminal angioplasty study (CAVATAS). A randomized trial. Stroke 2007;38(5):1526-30
9. Marks MP, Wojak JC, Al-Ali F et al. Angioplasty for symptomatic intracranial stenosis: clinical outcome. Stroke 2006: 37(4):1016-20
10. Qureshi AI, Hussein HM, El-Gengahy A et al. Concurrent comparison of outcomes of primary angioplasty and of stent placement in high-risk patients with symptomatic intracranial stenosis. Neurosurgery 2008 Apr 23 [Epub ahead of print]
11. Fiorella D, Levy EI, Turk AS et al. US multicenter experience with the wingspan stent system for the treatment of intracranial atheromatous disease: periprocedural results. Stroke 2007; 38(3):881-7
12. Zaidat OO, Klucznik R, Alexander MJ et al. The NIH registry on use of the Wingspan stent for symptomatic 70-99% intracranial arterial stenosis. Neurology 2008; 70(17):1518-24
13. Haley EC, Jr. Registries: they’re not just for weddings anymore. Neurology 2008; 70(17):1508-9

Cross References

Extracranial Carotid Angioplasty/Stenting, Regence Medical Policy Manual, Surgery, Policy No. 93

Percutaneous Venous Transluminal Angioplasty and Stenting, Regence Medical Policy Manual, Surgery, Policy No. 109 

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