1. Aetna considers percutaneous transluminal angioplasty of the extra-cranial carotid and vertebral arteries, with or without stent implantation and embolic protection, medically necessary in symptomatic individuals with at least 50% stenosis of the carotid artery or the vertebral artery.

2. Aetna considers percutaneous transluminal angioplasty, with or without stenting, of the intra-cranial arteries experimental and investigational for the treatment of either of the following conditions and all other indications because its effectiveness for these indications has not been established:

   1. Atherosclerotic stenosis of intra-cranial arteries; or

   2. Cerebral vasospasm after aneurysmal subarachnoid hemorrhage.

Angioplasty and stenting of extra-cranial arteries

Angioplasty and stenting of carotid and vertebral lesions represents a promising therapeutic option in patients at increased risk for surgical endarterectomy.  Endarterectomy has several limitations.  Among them, patients with severe coronary artery disease show a 3-fold increase in morbidity and mortality due to cardiac complications of the procedure.  Similarly, the risk of endarterectomy is increased in patients with carotid lesions that, due to their anatomic location, are difficult to approach surgically.  In addition, the risk of endarterectomy is increased in patients having previous cervical radiotherapy, previous endarterectomy, or lesions located or extending distally in the internal carotid artery.

There has been a high level of interest in treating extra-cranial carotid and vertebral stenoses with either angioplasty or stents.  The relative technical ease of performing such procedures has attracted considerable attention in the clinical community.  Such procedures are being performed in several academic medical centers.  A prospective, randomized, controlled, multicenter clinical trial designed to compare these endovascular interventions with the "gold standard" of surgical carotid endarterectomy is currently being conducted.

Although a recent study found that among patients with severe carotid artery stenosis and co-existing conditions (symptomatic carotid-artery stenosis of at least 50% of the luminal diameter or an asymptomatic stenosis of at least 80%), carotid stenting with the use of an emboli-protection device is not inferior to carotid endarterectomy (Yadav et al, 2004), the editorial accompanying this study stated that the small sample size and the study end points prevent conclusions regarding the relative roles of endarterectomy and carotid artery stenting in the treatment of carotid artery stenosis.  Physicians, industry sponsors, and regulatory agencies should insist on large scale, multi-center studies to ascertain the appropriate role of carotid artery stenting in patients in different clinical and anatomical subgroups.

Debette, et al. (2004) stated that carotid angioplasty and stenting (CAS) is sometimes used as an alternative to surgery, despite the lack of evidence for its safety and effectiveness.  These investigators concluded that CAS cannot be considered as a routine procedure and should be restricted to high-risk patients unfit for surgery.  Additionally, a recent Cochrane review (Coward, et al., 2004) on percutaneous transluminal angioplasty and stenting for carotid artery stenosis concluded that: "Data from randomised trials comparing endovascular treatment for carotid artery stenosis with carotid endarterectomy suggest that the two treatments have similar early risks of death or stroke and similar long term benefits.  However, the substantial heterogeneity renders the overall estimates of effect somewhat unreliable.  Furthermore, two trials were stopped early because of safety concerns, so perhaps leading to an over-estimate of the risks of endovascular treatment.  On the other hand, endovascular treatment appears to avoid completely the risk of cranial neuropathy.  There is also uncertainty about the potential for re-stenosis to develop and cause recurrent stroke after endovascular treatment.  The current evidence does not support a widespread change in clinical practice away from recommending carotid endarterectomy as the treatment of choice for suitable carotid artery stenosis.  There is a strong case to continue recruitment in the current randomised trials comparing carotid stenting with endarterectomy".

In a study on indications for intervention of atherosclerotic occlusive extra-cranial vertebral artery disease, Wehman et al (2004) reported that symptomatic patients with a single, causative extra-cranial atherosclerotic vertebral artery lesion that measures more than 50% stenosis by digital subtraction angiography receive treatment with angioplasty and stenting.

The Centers for Medicare and Medicaid Services (CMS) (2005) has determined that carotid artery stenting (CAS) with distal embolic protection is necessary for the following:

1. Patients who are at high risk for carotid endarterectomy and who also have symptomatic carotid artery stenosis > 70%. Medicare limits coverage to procedures performed using FDA approved carotid artery stenting systems and embolic protection devices;
2. Patients who are at high risk for carotid endarterectomy and have symptomatic carotid artery stenosis between 50% and 70%, in accordance with the Category B Investigational Device Exemption (IDE) clinical trials regulation, as a routine cost under Medicare’s clinical trials policy, or in accordance with the National Coverage Determination on carotid artery stenting post approval studies;
3. Patients who are at high risk for carotid endarterectomy and have asymptomatic carotid artery stenosis > 80%, in accordance with the Category B IDE clinical trials regulation, as a routine cost under Medicare’s clinical trials policy, or in accordance with the National Coverage Determination on carotid artery stenting post approval studies.
   

CMS defines patients at high risk for carotid endarterectomy as having significant co-morbidities and/or anatomic risk factors (i.e., recurrent stenosis and/or previous radical neck dissection), and would be poor candidates for carotid endarterectomy in the opinion of a surgeon.  For purposes of Medicare policy, significant co-morbid conditions include but are not limited to:

1. congestive heart failure (CHF) class III/IV;
2. left ventricular ejection fraction (LVEF) < 30%;
3. unstable angina;
4. contralateral carotid occlusion;
5. recent myocardial infarction (MI);
6. previous CEA with recurrent stenosis;
7. prior radiation treatment to the neck; and
8. other conditions that were used to determine patients at high risk for CEA in the prior carotid artery stenting trials and studies, such as ARCHER, CABERNET, SAPPHIRE, BEACH, and MAVERIC II.

According to CMS, symptoms of carotid artery stenosis include carotid transient ischemic attack (distinct focal neurological dysfunction persisting less than 24 hours), focal cerebral ischemia producing a non-disabling stroke (modified Rankin scale < 3 with symptoms for 24 hours or more), and transient monocular blindness (amaurosis fugax). CMS excludes patients who have had a disabling stroke (modified Rankin scale > 3) from eligibility for coverage of a carotid artery stent.

A CMS Decision Memorandum (2005) states that the degree of carotid artery stenosis should be measured by duplex Doppler ultrasound or carotid artery angiography and recorded in the patient medical records.  If the stenosis is measured by ultrasound prior to the procedure, then the degree of stenosis must be confirmed by angiography at the start of the procedure.  CMS states that if the stenosis is determined to be less than 70% by angiography, then CAS should not proceed.

A CMS Decision Memorandum (2007) states that "for patients who are at high risk for CEA surgery with asymptomatic carotid artery stenosis > 80%, several case series or registry reports and post-approval studies have been published since our prior decision which provided restricted coverage for these patients.  The basis of our restricted coverage in the prior decision was the undocumented natural history of asymptomatic stenosis on medical therapy (lack of a medical control group in past studies), the lack of long term data on CAS in these patients, and the lack of data on CAS performed outside the controlled trial setting.  While the outcomes of asymptomatic carotid artery stenosis with optimal medical therapy remain unclear and unstudied, the published reports provide evidence regarding our other prior concerns.  The observational studies by Halabi, Chaer, Park and Safian provided supporting evidence for CAS in patients with asymptomatic stenosis > 80%.  The post-approval studies, CAPTURE and CASES-PMS, provided additional evidence on 30-day outcomes and some information on 1 year outcomes.  The post-approval studies also showed that CAS outcomes were similar by provider volume (experience levels) and in settings outside clinical trials.  Unlike the situation with symptomatic patients, there were no trials or studies that raised concerns about the safety of CAS in asymptomatic patients with stenosis > 80%.

"With the published reports since our prior decision, CMS finds that the evidence is sufficient to conclude that PTA with carotid artery stenting improves health outcomes for patients who are at high risk for CEA surgery and have asymptomatic carotid artery stenosis > 80%.  With this, CMS proposes to remove the requirement that these procedures only be performed in a clinical trial or post approval study, based largely on the findings from CAPTURE and CASES-PMS.  As with the currently covered indications, facilities performing CAS for this patient group must meet the facility requirements outlined in this NCD.  As discussed above, CAS is not covered in the absence of distal embolic protection including those instances in which technical difficulties prevented deployment."

The CMS Decision Memorandum (2007) also states that "for patients who are > 80 years of age, there is mounting evidence that the rate of death, stroke and MI after CAS is higher than for patients < 80 years.  Stanziale and colleagues reported that octogenarians had a significantly higher rate of stroke, death or MI than nonoctogenarians (9.2% versus 3.4%, respectively; p = 0.024).  Safian and colleagues reported data that showed patients > 75 years had higher adverse outcomes than patients < 75 (7.6% versus 4.8%).  CAPTURE showed that patients > 80 years of age had significantly higher rates of death, stroke or MI at 30 days than patients < 80 years (9.4% versus 5.3%, respectively; statistically significant, p-value < 0.0001).  SPACE found that patients > 75 years of age had a significantly higher rate of ipsilateral ischemic stroke and death at 30 days compared to patients > 75 (11.01% versus 5.92%; exceeding the non-inferiority margin).  Outcomes by age were not specifically reported by Chaer, Halabi, Mas and Park.

"The consistency of these findings across the trials and studies, observed in both symptomatic and asymptomatic patients, creates concerns for the safety of older patients undergoing CAS.  This is also consistent with the recognition that patients > 80 years of age are at higher risk for CEA.  These patients were specifically excluded from the NASCET and ACAS trials.  This was also one of the high risk criteria in the SAPPHIRE trial for carotid revascularization in general.  The higher incidence of adverse outcomes is particularly concerning for patients who have asymptomatic stenosis.  In many of these patients, more harm than good would have come from the PTA and CAS procedure.  Given the evidence, CMS proposes to continue the restriction that CAS for asymptomatic patients with stenosis > 80% and who are > 80 years of age be covered only in the setting of a clinical trial or post approval study for safety purposes.  In addition, CMS proposes to expand this restriction to include symptomatic patients with stenosis > 70% and who are > 80 years of age".

Angioplasty and stenting of intra-cranial arteries for the treatment of atherosclerotic stenosis:

Although atherosclerotic stenoses of the intra-cranial vessels are less frequent than those of the extra-cranial vessels, they are associated with a high risk for stroke that is the third leading cause of death in the United States.  Atherosclerotic stenosis of intra-cranial arteries is usually treated with medication (e.g., acetyl salicylic acid, clopidogrel, and ticlopidine).  It has also been reported recently that cilostazol, a phosphodiesterase inhibitor, can prevent the progression of intra-cranial arterial stenosis (Kwon et al, 2005).  When pharmacotherapies fail to improve symptoms, balloon angioplasty has been reported to be useful.  However, this surgical procedure is associated with a significant risk of complications (e.g., acute occlusion or symptomatic dissection, re-stenosis, and stroke).  It has also been reported that stenting could reduce the rate of re-stenosis following balloon angioplasty of intra-cranial arteries.  However, the clinical benefit of balloon angioplasty, with or without stenting, has not been firmly established.

In a retrospective case series study, Lylyk et al (2005) discussed their experience in the treatment of patients with symptomatic intra-cranial atherosclerotic stenoses that are refractory to medical therapy, and who underwent stent-assisted angioplasty (n = 104).  Patient records were analyzed for location and degree of stenosis, regimen of anti-platelet agents, devices used, procedure-related complications and adverse events.  Clinical (Modified Rankin Scale) and radiographical outcomes were obtained 24 hours, 1 month and 3 to 6 months after treatment.  A total of 65 lesions (62.5%) were located in the posterior circulation.  Mean stenosis was 75.4%.  In all patients, the angiographical degree of stenosis was reduced to less than 30%.  One stent was implanted in 66 patients (63%), and 2 or more in 38 patients (37%).  Modified Rankin Scale was 1 to 2 in 67.5% of the cases, 3 to 4 in 25.9%, 5 in 2.8%, and 6 in 3.8%.  Procedural morbidity was 5.7%, while procedural mortality was 3.8%.  Angiographical follow-up was available in 58 patients (55.7%) and the rate of re-stenosis was 12.5%.  These investigators concluded that in selected patients, endovascular revascularization of intra-cranial arteries by means of stent-assisted angioplasty is technically feasible, effective and safe.

In an uncontrolled study, Yu and associates (2005) reported their findings on 18 patients who underwent stenting for symptomatic basilar artery stenosis.  There were 3 major peri-procedural complications (16.7%) without fatality.  At a mean follow-up of 26.7 months, 15 patients (83.3%) had an excellent long-term outcome.  Only 1 patient (5.6%) had moderate disability from recurrent stroke, and 2 patients died of medical illness at 30 and 36 months after stenting.  There were several limitations in this case series report: (i) it is a retrospective study in which patients were stented empirically without standard inclusion and exclusion criteria creating possible selection bias, (ii) not every patient received maximal medical therapy before stenting, and (iii) these are single-center data, and may not be generalizable for reasons of referral and selection bias, neurointerventional physicians’ expertise, and multi-disciplinary care.  These authors stated that because of the poor prognosis of symptomatic basilar artery stenosis found in previous studies, prospective multi-center randomized controlled studies of endovascular basilar artery stenting are warranted despite the risk of major procedural complications.

In a retrospective study, Marks and colleagues (2005) assessed their findings on 36 patients with 37 symptomatic atherosclerotic intra-cranial stenoses who underwent primary balloon angioplasty.  All patients had symptoms despite medical therapy.  A total of 34 patients were available for follow-up (mean of 52.9 months, range of 6 to 128 months).  Mean pretreatment stenosis was 84.2% before angioplasty and 43.3% after angioplasty.  The peri-procedural death and stroke rate was 8.3% (2 deaths and 1 minor stroke).  Two patients had strokes in the territory of angioplasty at 2 and 37 months following angioplasty.  The annual stroke rate in the territory appropriate to the site of angioplasty was 3.36%, and for those patients with a residual stenosis of greater than or equal to 50% it was 4.5%.  Patients with iatrogenic dissection (n = 11) did not have transient ischemic attacks or strokes after treatment.  These investigators concluded that results of long-term follow-up suggest that intra-cranial angioplasty without stent placement reduces the risk of further stroke in symptomatic patients.

On the other hand, Hauth and colleagues (2004) found that angioplasty of intra-cranial arteries can be associated with life-threatening complications.  These investigators ascertained the feasibility and safety of angioplasty or angioplasty and stenting of extra- and intra-cranial vertebral artery (VA) stenosis.  In 16 consecutive patients (9 men, 7 women; mean age 61 years, range 49 - 74 years) 16 stenotic VAs were treated with angioplasty or angioplasty and stenting.  Eleven stenoses were localized in V1 segment, 1 stenosis in V2 segment and 4 stenoses in V4 segment of VA.  Fourteen VA stenoses were symptomatic, while 2 were asymptomatic.  The etiology of the stenoses was atherosclerotic in all cases.  Angioplasty was performed in 8/11 V1 and 2/4 V4 segments of the VA.  In 3/11 V1 segments and 2/4 V4 segments of the VA, combined angioplasty with stenting were used.  The procedures were successfully performed in 14/16 VAs (87%).  Complications were asymptomatic vessel dissection resulting in vessel occlusion in 1/11 V1 segments and asymptomatic vessel dissection in 2/4 V4 segments of the VA.  One patient died in the 24-hr period after the procedure because of subarachnoid hemorrhage as a complication following vessel perforation of the treated V4 segment.  These authors concluded that angioplasty or angioplasty in combination with stenting of extra-cranial VA stenoses can be performed with a high technical success rate and a low complication rate.  However, in intra-cranial VA stenosis the procedure is technically feasible but complications can be life-threatening.  The durability and procedural complication rates of primary stenting without using pre-dilation in extra- and intra-cranial VA stenosis should be defined in the future.  Moreover, in a review on vertebrobasilar disease, Savitz and Caplan (2005) noted that preliminary results of angioplasty or stenting of occlusive VA lesion in the neck reveal that re-stenosis is more common than with carotid artery stenting.  The small diameter and angulation of the VA origin complicate endovascular treatment.  Intra-cranial vertebral and basilar artery angioplasty and stenting have produced mixed results.  It is also interesting to note that Boulos and colleagues (2005) stated that placement of intra-cranial and extra-cranial drug-eluting stent appears to be a safe alternative to the medical management of atherosclerotic disease of the vertebrobasilar and carotid systems.  Moreover, these researchers concluded that further randomized studies are needed to ascertain the safety and effectiveness of this procedure.  These observations are in agreement with those of Gupta et al (2003), Doerfler et al (2004), Kim et al (2004), Komotar et al (2005), as well as Hartmann and Jensen (2005).

In a retrospective study (21 intra-cranial lesions in 18 patients), Gupta and associates (2003) reported that endovascular revascularization of intra-cranial vessels is technically feasible and may be performed successfully.  However, peri-procedural complication and fatality rates in neurologically unstable patients are high.  Endovascular re-vascularization was performed on 8 distal internal carotid artery lesions, 6 middle cerebral artery lesions, 4 intra-cranial VA lesions, and 3 basilar artery lesions.  Re-canalization was complete in 5 arteries (Thrombolysis in Myocardial Infarction [TIMI] Grade III), partial in 14 arteries (TIMI Grade II), and complete occlusion (TIMI 0) developed in 1 artery.  In a patient with a tight basilar stenosis, no angioplasty could be performed because of the inability to cross the stenosis with the guide wire.  Major peri-procedural complications occurred in 9 (50%) patients: intra-cranial hemorrhage in 3 (17%), disabling ischemic stroke in 2 (11%), and major extra-cranial hemorrhage in 4 (22%).  Three patients died: 1 from intra-cerebral hemorrhage and 2 from cardiopulmonary failure.  These investigators suggested that patient selection, procedure timing, and peri-procedural medical management are critical factors to reduce peri-procedural morbidity and mortality.

In a review on endovascular treatment of cerebrovascular disease, Doerfler et al (2004) stated that angioplasty and stenting of intra-cranial atherosclerotic disease is feasible but remains a high-risk procedure, indicated only in highly selected patients.  These investigators noted that advances in endovascular therapy have occurred in all areas of cerebrovascular disease.  They further stated that to obtain maximal patient benefit, endovascular treatment should be performed as an inter-disciplinary approach in high-volume centers; and concluded that long-term follow-up review is needed to clarify the overall role of endovascular treatment in the management of patients with cerebrovascular disease.  Furthermore, Kim and associates (2004) stated that although stent-assisted angioplasty is an effective treatment for coronary and peripheral arterial disease, its effectiveness in intra-cranial arteriosclerotic disease has not been verified.  They evaluated the radiographical and clinical outcome of stent-assisted angioplasty for symptomatic middle cerebral artery (MCA) stenosis (n = 14).  Patients had symptomatic high-grade stenosis (greater than 60%) on the proximal portion of the MCA, and had experienced either recurrent transient ischemic attacks (TIAs) resistant to medical therapy or one or more stroke attacks.  Stent-assisted angioplasty was successfully performed in 8 of 14 patients without any serious complications and unsuccessful in 2 of 14 patients due to the tortuous curve of the internal carotid artery siphon.  Four patients had complications: 2 had an arterial rupture (1 was rescued by an additional stent and balloon tamponade, the other patient died); the remaining 2 patients had thrombotic occlusion and distal thrombosis.  Residual stenosis was less than 50% in diameter in all patients.  All 8 patients who underwent follow-up cerebral angiography had no re-stenosis.  Follow-up single photon emission computed tomography demonstrated improved perfusion in the affected MCA territory in all subjects with TIA and in 1 of 3 stroke patients.  Using the Modified Rankin Scale at follow-up, 4 of 5 TIA patients and 5 of 6 stroke patients were deemed functionally improved or having a stable clinical status.  These authors concluded that although the re-stenosis rate in stent-assisted angioplasty seems to be better than in primary balloon angioplasty as reported previously, the complication rate is still high.  Elective stenting is an alternative therapeutic method for the prevention of secondary ischemic stroke in stroke patients with MCA stenosis, and seems to be a potentially effective but also hazardous therapeutic technique in patients with recurrent TIAs.  These investigators concluded that the findings of this study indicate the need for randomized control studies of this intervention.  In addition, long-term follow-up data and additional clinical experience are needed to determine the durability of this procedure.

In a review on endovascular treatment options for intra-cranial carotid artery atherosclerosis, Komotar et al (2005) stated that novel stent technology represents the beginning of innovative methods that will be employed by endovascular neurosurgeons to treat intra-cranial atherosclerosis.  However, more clinical trials, especially those that compare stenting with the best medical management available are needed to ascertain the effectiveness and appropriateness of this technique.  These investigators concluded that “angioplasty with stent placement carries risks along with a significant rate of restenosis; however, advancements in technology and methodology have begun to address these issues.  In short, endovascular methods have revolutionized the treatment of this disease.  With continued experience and a multidisciplinary approach in the evaluation of these patients, favorable outcomes may be achieved”.

In a review on conventional, direct, and staged stenting for high-grade stenoses involving the posterior intra-cranial circulation, Levy and associates (2005) stated that for patients with high-grade posterior circulation intra-cranial stenoses involving the perforator-rich zones of the basilar artery, staged stenting may reduce procedure-related morbidity.  A staged approach allows for plaque stabilization resulting from post-angioplasty fibrosis, which may protect patients from "snow-plowing," embolic shower of debris, or dissection.  The authors noted that further clinical, in vivo, and histological investigation is warranted.  In a review on recent advances in angioplasty and stenting of intra-cranial atherosclerotic stenosis, Hartmann and Jansen (2005) stated that “intracranial angioplasty with or without stenting is a promising treatment option.  Patient selection, careful periprocedural medical management, and a highly skilled neuroendovascular surgeon are all required to perform the procedure with an acceptable risk.  If stenting is to be shown to be a safe therapeutic alternative, prospective trials comparing stenting with optimal medical treatment need to be performed”.  Furthermore, a recent Cochrane review (Coward et al, 2005) concluded that there is currently inadequate evidence to evaluate the effectiveness of percutaneous transluminal angioplasty, with or without stenting, or primary stenting for the treatment of VA stenosis.

Through Humanitarian Device Exemptions, the U.S. Food and Drug Administration (FDA) approved two intra-cranial stent systems: (i) the Neurolink System (Guidant Corporation) in August 2002, and (ii) the Wingspan Stent System with Gateway PTA Balloon Catheter (Boston Scientific Corporation) in August 2005.  The former is indicated for the treatment of patients with recurrent intra-cranial stroke caused by atherosclerotic disease refractory to pharmacotherapies, in intra-cranial vessels ranging from 2.5 to 4.5 mm in diameter with greater than or equal to 50 % stenosis that are accessible to the stent system.  The latter is indicated for improving cerebral artery lumen diameter in patients with intra-cranial atherosclerotic disease, refractory to pharmacotherapies, in intra-cranial vessels with greater than or equal to 50 % stenosis that are accessible to the system.

Although approved by the FDA, the clinical effectiveness of these two intra-cranial stent systems has not been clearly established.  In a multi-center, non-randomized, prospective feasibility study, the Stenting of Symptomatic Atherosclerotic Lesions in the Vertebral or Intracranial Arteries (SSLYVIA) Study group (2004) assessed the Neurolink System for the treatment of patients with vertebral or intra-cranial artery stenosis.  In 61 patients enrolled in this study, 43 (70.5%) intra-cranial arteries (15 internal carotid, 5 middle cerebral, 1 posterior cerebral, 17 basilar, 5 vertebral) and 18 (29.5%) extra-cranial VAs (6 ostia, 12 proximal to the posterior inferior cerebellar artery [PICA]) were treated.  In the first 30 days, 4 patients (6.6%) had strokes and no deaths occurred.  Successful stent placement was achieved in 58/61 cases (95%).  At 6 months, stenosis of greater than 50 % occurred in 12/37 (32.4%) intra-cranial arteries and 6/14 (42.9%) extra-cranial VAs, 4 in the vertebral ostia.  Seven (39%) recurrent stenoses were symptomatic.  Four of 55 patients (7.3%) had strokes later than 30 days, 1 of which was in the only patient not stented.  These investigators concluded that the Neurolink System is associated with a high rate of successful stent deployment.  Strokes occurred in 6.6% of patients within 30 days and in 7.3% between 30 days and 1 year.  Although re-stenoses occurred in 35% of patients, 61% were asymptomatic, the authors stated that more studies involving the Neurolink System are warranted.

The FDA’s approval of the Wingspan Stent System was based on an international safety study of 45 patients who had a stroke caused by an intra-cranial lesion and for whom medical treatment failed to prevent another stroke.  The device had a stent success rate of 100%, a procedural success rate of 97.7%, and a 4.4% incidence of death or stroke in the ipsilateral hemisphere of the brain as the lesion at 30 days post-procedure.  The incidence of death or same hemisphere stroke at 6-month follow-up was 7.0% (Kofol and Donovan, 2005).  This encouraging preliminary finding needs to be validated by further randomized controlled trials. 

In a Cochrane review on angioplasty for intra-cranial artery stenosis , Cruz-Flores and Diamond (2006) concluded that there is currently insufficient evidence to recommend angioplasty with or without stent placement in routine practice for the prevention of stroke in patients with intra-cranial artery stenosis.  The descriptive studies showed that the procedure is feasible although it carries a significant morbidity and mortality risk.  Evidence from randomized controlled trials is needed to evaluate the safety and effectiveness of angioplasty in preventing recurrent stroke.  This is in agreement with the observation of Higashida and Meyers (2006) who stated that "at this time, patients with significant intracranial stenosis should receive counseling on the benefits and risks of revascularization therapy.  Ultimately, determination of which patients should undergo revascularization procedures will require carefully planned, randomized clinical trials".

An assessment by the National Institute for Health and Clinical Excellence (NICE, 2007) concluded: "The evidence on clinical efficacy of endovascular stent insertion for intracranial atherosclerotic disease is currently inadequate and the procedure poses potentially serious safety concerns. Therefore, clinicians should collaborate to organise randomised studies of adequate size to compare endovascular stent insertion for intracranial atherosclerotic disease against best medical management. These studies should clearly define patient selection and be designed to provide outcome data based on follow-up of at least 2 years." The Specialist Advisors to NICE considered this procedure to be of uncertain safety with potential adverse effects including death, stroke, arterial dissection, vessel occlusion, vessel rupture, hemorrhage, restenosis and stent thrombosis.

The Centers for Medicare & Medicaid Services (CMS, 2008) reconsidered their prior decision on intracranial PTA and stenting in November 2006, and announced their decision to maintain their position that this is a promising but unproven therapy. CMS reviewed five studies (Bose, et al., 2007; Fiorella, et al., 2007; Levy, et al., 2007; Layton, et al., 2008; Zaidat, et al., 2008) published since their last review that presented data using the Wingspan stent system. CMS noted that the study by Bose, et al. (2007) presented data that was submitted to the FDA, and was considered in CMS' prior decision memorandum.

CMS observed that three of the new studies report on registry data; CMS noted that, as with all case series type studies, these studies are difficult to interpret without additional studies that reduce the possibility of inherent biases and substantiate the clinical findings. The studies by Fiorella, et al. (2007) and Levy, et al. (2007) presented data from the Wingspan registry of 78 patients. Zaidat and colleagues (2008) reported on the National Institutes of Health (NIH) Wingspan registry of 129 patients. CMS stated that various biases may have been factors in the observed differences in the registry data compared to the initial Wingspan study presented by Bose, et al. (2007). Levy and colleagues (2007) reported: “The ISR (in-stent restenosis) rate with the Wingspan stent is higher in our series than previously reported, occurring in 29.7% of patients.” CMS found, in addition, that the lack of control groups and long term follow-up add to the uncertainty of clinical benefit. The CMS decision memorandum also expressed concern that Levy et al. (2007) considers in-stent dissections to be “clinically silent,” particularly in view of their treatment with a second stent. The CMS decision memorandum also pointed out that concerns were also noted by Kallmes and Cloft (2008) who reported: “The overall restenosis rate in the study by Levy et al. was 31%, even though they excluded 4 cases of complete occlusion. Including those cases of complete occlusion would have increased the reported rate of restenosis by approximately 4%.” The CMS decision memorandum also found that a higher restenosis rate (25%) and adverse outcome rate (14%) were also seen in the analysis by Zaidat and colleagues (2008), although the patients enrolled in the NIH registry had greater stenosis (70-99%) compared to the other registry.

CMS concluded that "[g]iven the invasive nature of this treatment and the severe risks, as noted by Fiorella and colleagues, a well designed, well conducted randomized controlled trial is needed." In supporting the need for a clinical trial, the CMS decision memorandum cited Derdeyn and Chimowitz (2007) who stated: “At present, however, there is no level 1 evidence to support angioplasty and stenting for patients who have symptomatic intracranial atherosclerotic disease. Case series suggest that the safety and stroke risk reduction of this procedure may provide a benefit, particularly with self-expanding stent technology. A randomized, controlled trial is needed to prove the efficacy of this therapy.” The CMS decision memorandum also cited Kallmes and Cloft (2008), who wrote: “We, the community of physicians, really have to continue to ponder what the real value of Wingspan is, and we must demand more data about safety and efficacy relative to other treatment options.”

CMS concluded that it "believes the evidence is promising and strongly encourages the development and completion of randomized controlled trials and currently covers PTA and stenting for the treatment of intracranial artery stenosis greater than or equal to 50 percent in patients with atherosclerotic disease when furnished in accordance with the FDA-approved protocols governing Category B IDE clinical trials." The CMS decision memorandum noted that there is a newly funded clinical trial titled “Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS)” designed to determine health outcomes comparing optimal medical therapy to stenting and includes a 2 year mean follow-up. CMS stated that this randomized trial "is expected to provide solid evidence on this intervention."

In summary, although there is preliminary evidence that balloon angioplasty, with or without stenting, may be effective in treating symptomatic patients with intra-cranial stenoses, available data are mainly from retrospective case series.  Randomized controlled studies are needed to ascertain the effectiveness of this technology compared to best medical care in preventing stroke in patients with intra-cranial stenosis that is symptomatic or asymptomatic.  Other parameters that need to be addressed are: (i) the frequency of peri-procedural stroke (disabling and non-disabling), death, and the combination of stroke and death, (ii) the frequency of other major peri-procedural complications that require additional therapy, prolonged hospital stay or death as well as minor complications (e.g., hematoma, wound infection, and nerve palsy), (iii) the frequency of stroke in the territory of the stenosed vessels, (iv) the frequency of re-stenosis in the involved vessels, and (v) the frequency of hospital resource use, including length of stay and frequency of re-admission.

Angioplasty and stenting of intracranial arteries for the treatment of cerebral vasospasm after aneurysmal subarachnoid hemorrhage:

Aneurysmal subarachnoid hemorrhage (SAH) is a common form of stroke.  Frequently, a significant number of patients with this condition develop angiographical or clinical vasospasm with devastating consequences.  The pathogenesis of cerebral vasospasm following SAH remains unclear despite extensive research.  Due to the lack of a clear etiology, medical treatment is still largely limited to hypertensive-hypervolemic-hemodilution (triple-H) therapy, and calcium channel blockers (e.g., nimodipine).  Cerebral vasospasm that has become refractory to maximal medical therapy can be treated with intra-arterial infusion of vasodilators (e.g. papaverine).  Moreover, recent advent in the field of interventional neurology and the development of minimally invasive techniques has resulted in expansion of potential therapeutic approaches for cerebral vasospasm secondary to aneurysmal SAH (Kosty, 2005).  Balloon angioplasty is being investigated as a treatment option in patients with vasospasm following aneurysmal SAH; however its effectiveness for this indication has yet to be established.

In a case reports study, Murayama et al (2003) assessed the safety and effectiveness of combined Guglielmi detachable coil (GDC) embolization and balloon angioplasty in a single session for the treatment of ruptured aneurysms associated with symptomatic vasospasm (n = 12).  Patients underwent GDC aneurysm occlusion and balloon angioplasty (n = 6), intra-arterial papaverine infusion (n = 2), or both (n = 4) in a single session.  In 9 patients, aneurysm coil occlusion was performed first.  Complete GDC occlusion was achieved in 8 patients, a small neck remnant persisted in 3, and embolization was incomplete in 1 patient.  In all subjects, angiographical improvement of cerebral vasospasm was obtained.  In 1 subject, a thromboembolic complication occurred and was treated with urokinase.  Clinical outcomes at discharge were good recovery in 6, moderate disability in 2, severe disability in 3, and death in 1.  These researchers concluded that endovascular treatment can be the first therapeutic option for ruptured aneurysms associated with severe vasospasm on admission.  It offers some advantages over surgery in this setting, but these are balanced by the risk of thromboembolism.  This is in agreement with the observation of Wijdicks et al (2005) who noted in their review that balloon angioplasty is a durable means of alleviating arterial narrowing and preventing stroke in patients with symptomatic vasospasm following aneurysmal SAH.  However, the procedure has risks, especially in inexperienced hands.  Additionally, the timing of endovascular intubation and use of inotropes in patients with cardiac dysfunction are unresolved issues.

In a review on cerebral vasospasm after SAH, Janjua and Mayer (2003) stated that the care management of this condition has evolved significantly over the past 10 years, with many new diagnostic modalities and promising treatments (e.g., balloon angioplasty) now available.  These researchers concluded that clinical trials are needed to assess the effectiveness of these new techniques and to further define the optimal management of this often devastating complication following SAH.  This is in agreement with the observation of Rabinstein and colleagues (2004).  These investigators reviewed 81 consecutive patients with symptomatic cerebral vasospasm from aneurysmal SAH treated with percutaneous balloon angioplasty or selective intra-arterial papaverine infusion (105 procedures).  Mean patient age was 54 years (range, 29 - 88 years).  Twenty-nine patients (36%) presented with poor-grade (World Federation of Neurologic Surgeons [WFNS] grade IV or V) SAH.  Clinical deficits were global in 55 patients (70%), and angiographic vasospasm was diffuse in 53 (65%).  Endovascular treatment consisted of transluminal angioplasty alone (18 procedures, 17%), intra-arterial papaverine infusion (65 procedures, 62%), or both (22 procedures, 21%).  Unequivocal arterial dilatation was achieved in all but 2 patients, and major complications occurred in 2% of the procedures.  Ten patients (12%) died in the hospital, and 36 (44%) recovered poorly.  Permanent deficits attributable to cerebral vasospasm were present in 37 patients (52% of survivors).  On multivariate logistic regression analysis, advanced age and poor WFNS grade at presentation were predictive of poor clinical outcome.  These authors stated that balloon angioplasty and intra-arterial papaverine are promising treatments for severe symptomatic vasospasm following SAH.  They also noted that advanced age and poor clinical status (WFNS grade IV or V) at the time of SAH onset are predictive of poor clinical outcome despite endovascular treatment with balloon angioplasty or intra-arterial papaverine in patients with symptomatic vasospasm.

In a retrospective study, Turowski et al (2005) reported that in experienced hands, intra-cranial angioplasty is a feasible and safe option in a selected group of patients with severe (over 50% stenosis) symptomatic vasospasm following SAH.  Cerebral circulation time is a surrogate parameter closely linked to cerebral perfusion.  This study showed that not only stenosis but also changes in circulation time were obtained by angioplasty.  A total of 20 angioplasties of 1 or 2 vessel segments were performed over 2 years in 18 consecutive patients with post-hemorrhagic vasospasm.  In all patients, degree of stenosis and circulation time could be reduced by angioplasty.  Clinical results were ranked according to Glasgow Outcome Scale.  Imaging after 15/20 angioplasties showed no additional infarction.  In 4/20 cases, computed tomography (CT) showed demarcation of infarction after angioplasty.  In 1/20 cases of posterior circulation angioplasty, CT is not sensitive enough to exclude smaller infarctions.

In a clinical trial, Murai and associates (2005) examined the long-term effects of transluminal balloon angioplasty (TBA) on cerebral blood flow (CBF) and the functional properties of the arterial wall after aneurysmal SAH.  A total of 12 patients underwent unilateral TBA.  Xenon-enhanced CT was performed for an average of 18 days after TBA to measure CBF and cerebrovascular reactivity (CVR).  Cerebral blood flow and CVR were compared between the side of TBA and the contralateral side.  A total of 19 vascular territories were treated successfully with TBA in the subjects.  Angiographical improvement of vasospasm was demonstrated in all 12 patients, and 9 (75 %) patients showed neurological improvement.  After TBA, global CBF was 35.1 +/- 8.2 mL/100 g per minute, with CBF on the side with TBA (37.8 +/- 10.3 mL/100 g per minute) being essentially the same as that on the other side (p = 0.0671, paired Student t test).  Likewise, reactivity to acetazolamide did not differ significantly between sides (p = 0.0817).  These investigators concluded that TBA increased proximal vessel diameters but showed no significant influence on CBF or CVR 3 weeks later.  Benefits presumably were short-term, but the procedure was clinically safe.

Balloon angioplasty is also being used prophylactically for patients with cerebral vasospasm following SAH (Janjua and Mayer, 2003; Wu et al, 2004).  A phase II clinical trial is ongoing at 5 centers comparing the outcomes of transluminal balloon prophylaxis with those of conventional medical management in patients with aneurysmal SAH who are at high risk for vasospasm (the Internet Stroke Center, 2004). 

In summary, while there is some preliminary evidence from retrospective case series studies that balloon angioplasty may be beneficial in treating cerebral vasospasm following aneurysmal SAH, its effectiveness in the prevention and treatment of this condition need to be verified by prospective, randomized, controlled trials.