Technology Evaluation
Center (TEC)

Angioplasty and Stenting of the Cervical Carotid Artery
with Embolic Protection of the Cerebral Circulation

EXECUTIVE SUMMARY

Background.  Atherosclerotic lesions in the cervical carotid artery can increase the risk of disabling or fatal ischemic stroke.  While carotid endarterectomy (CEA) can diminish this risk, it trades immediate procedure-related stroke and death for a reduction in stroke risk experienced over subsequent years.  Whether the tradeoff is likely to benefit an individual patient is determined by the:

1.  magnitude of risk reduction accompanying CEA compared to best medical therapy;

2.  periprocedural risk of stroke or death; and

3.  patient life expectancy.

Results from several landmark trials have established upper limits for periprocedural death/stroke rates that must be achieved for CEA to be accompanied by a net clinical benefit.  Because presence or absence of symptoms and the degree of stenosis influence the potential for benefit or harm, these limits differ according to symptomatic status and degree of stenosis.

Carotid angioplasty and stenting (CAS) with an embolic protection device (EPD) is a recently introduced procedure also used to treat carotid artery stenosis.  U.S. Food and Drug Administration (FDA) labeling approves use only in patients with medical comorbidities associated with potentially increased periprocedural CEA risk or anatomy unfavorable for CEA. 

Objective.  To review and evaluate available evidence concerning outcomes of CAS with EPD alone and compared to CEA and best medical therapy in patients with carotid artery stenosis.  The Assessment specifically seeks evidence to address the following questions:

1.  Is the periprocedural death/stroke rate with CAS less than 3% for asymptomatic and less than 6% for symptomatic patients?

2.  For those subgroups defined by a) medical comorbidities or b) unfavorable anatomy, are periprocedural death/stroke rates with CAS less than 3% for asymptomatic and less than 6% for symptomatic patients?

3.  How do the benefits and harms of CAS, CEA, and best medical therapy compare?

Search strategy.  MEDLINE® was searched (via PubMed) for articles indexed under the MeSH® headings "stents" AND "carotid artery diseases" OR "carotid stenosis" from 1994 through December 2009 and was limited to articles published in English that reported on human subjects.  Additionally, clinicaltrials.gov was searched with terms "carotid" and "angioplasty".

Selection criteria.  Randomized, controlled trials and prospective multicenter registries with predefined endpoints.

Main results.  Three randomized, controlled trials compared CAS directly to CEA (with best medical therapy) using a noninferiority approach.  The "Stent-Protected Angioplasty versus Carotid Endarterectomy" (SPACE) and "Endarterectomy versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis" (EVA-3S) trials enrolled recently symptomatic patients with >50% and >60% stenosis respectively, while the "Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy" trial (SAPPHIRE) enrolled symptomatic (>50% stenosis) and asymptomatic (>80% stenosis) patients at with medical comorbidities or unfavorable anatomy—stratifying randomization according to the presence or absence of symptoms.  None of the trials met targeted enrollments. 

SPACE and EVA-3S were terminated early:  SPACE due to lack of funding and a larger-than-anticipated projected sample size; EVA-3S for reasons of safety and futility.  Neither demonstrated noninferiority.  Periprocedural death/stroke rates with CAS in both trials exceeded those established as clinically acceptable and associated with an overall net clinical benefit for symptomatic patients: in SPACE, 7.7% (95% CI: 6.1–9.7); in EVA-3S, 9.6% (95% CI: 6.4–14.0). Post-procedure, ipsilateral stroke rates were low in both SPACE and EVA-3S.  In SPACE, from day 31 through 2 years, rates of ipsilateral stroke were 2.2% following CAS and 1.9% following CEA.  Ipsilateral stroke rates in EVA-3S from day 31 through 4 years were 1.3% and 2.0% following CAS and CEA, respectively.   In SAPPHIRE from day 31 through 3 years, ipsilateral stroke were 4.4% and 3.6% following CAS and CEA, respectively.

SAPPHIRE found CAS to be noninferior to CEA for a composite primary endpoint of death, stroke, myocardial infarction (MI) to 30 days or ipsilateral stroke day 31 to 1 year.  The dominant difference between arms was MI occurrence—almost all non-Q wave.  Few symptomatic patients were enrolled (fewer than 50 in each arm).  The 5.1% (95% CI: 2.4 to 10.7) and 3.3% (95% CI: 1.3 to 8.2) periprocedural stroke rates among asymptomatic patients undergoing CAS and CEA respectively, exceeded the 3% death/stroke rate established as clinically acceptable and associated with an overall net clinical benefit.  After 3 years' follow-up, no meaningful differences were found in outcomes between CAS and CEA.

Results were available from 18 multicenter, prospective registries collectively enrolling 20,194 patients, arguably the most generalizable and applicable evidence available for outcomes following CAS.  Eleven registries enrolled patients in accordance with FDA labeling and 30-day outcomes were available according to symptomatic status (13,783 asymptomatic and 3,353 symptomatic).  In nine registries, 30-day death/stroke rates were either reported or obtained from investigators; in the remaining two death/stroke rates were estimated from 30-day death/stroke/MI and MI rates.  For asymptomatic patients, the pooled periprocedural death/stroke rate was 3.9% (95% CI: 3.3–4.4); for symptomatic patients 7.4% (95% CI: 6.0–9.0).  Combined data from 2 registries reported acceptable periprocedural death/stroke rates for patients with unfavorable anatomy, but included only 371 asymptomatic and 60 symptomatic patients.  No other registry reported results by symptomatic status for those subgroups.

Author's Conclusions and Comments.  In patients selected because of medical comorbidities and/or unfavorable anatomy, there is generalizable and applicable evidence that CAS is performed with periprocedural death/stroke rates exceeding 3% for asymptomatic and 6% for symptomatic patients and therefore not accompanied by net clinical benefit. 

SUMMARY OF APPLICATION OF THE TECHNOLOGY EVALUATION CRITERIA

Based on the available evidence, the Blue Cross and Blue Shield Association Medical Advisory Panel (MAP) made the following judgments about whether carotid artery angioplasty and stenting (CAS) with embolic protection devices (EPD) meets the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria to reduce stroke risk from symptomatic or asymptomatic carotid stenosis.

1.  The technology must have final approval from the appropriate governmental regulatory bodies.

CAS with EPD is a procedure and thus does not require U.S. Food and Drug Administration (FDA) approval.  However, the devices used for CAS and for EPD require FDA approval.  A number of manufacturers' stents and EPDs are FDA-approved and indicated specifically for use in carotid arteries.  The FDA has mandated postmarketing studies for these devices, including longer follow-up for patients already reported to the FDA, and additional registry studies primarily to compare outcomes as a function of clinician training and facility experience.  The devices are indicated for combined use of a stent and EPD to reduce stroke risk in patients with medical comorbidities or unfavorable anatomy who are symptomatic with 50% or greater stenosis or asymptomatic with 80% or greater stenosis.  CAS for patients outside these indications is an off-label use.

2.  The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes.

Available evidence permits conclusions regarding periprocedural complication rates (particularly death or stroke) following CAS among symptomatic or asymptomatic patients treated under current FDA labeling.  Periprocedural death/stroke rates exceed those established as clinically acceptable and associated with a net clinical benefit following CEA.  There is limited evidence and a clinical rationale to suggest CAS may be beneficial in the subgroup of patients with unfavorable anatomy.  However, because outcomes have been reported only for a small number of patients, the accompanying uncertainty is substantial.  Thus, evidence is insufficient to define possible benefit in this subgroup with unfavorable anatomy.

3.  The technology must improve the net health outcome.

Available evidence supports concluding that CAS with EPD does not improve the net health outcome.

4.  The technology must be as beneficial as any established alternatives.

Available evidence supports concluding that CAS with EPD is not as beneficial as: 1) best medical therapy for symptomatic or asymptomatic patients with medical comorbidities or unfavorable anatomy; or 2) CEA for symptomatic patients without medical comorbidities or unfavorable anatomy.  Whether CAS with EPD is as beneficial as CEA or medical therapy for asymptomatic patients without medical comorbidities or unfavorable anatomy cannot be determined because available evidence is insufficient to permit conclusions.

5.  The improvement must be attainable outside the investigational settings.

CAS with EPD has not been demonstrated to improve health outcomes in the investigational setting.

Based on the above, use of carotid artery angioplasty and stenting with embolic protection of the cerebral circulation for patients with carotid artery stenosis does not meet the TEC criteria.

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NOTICE OF PURPOSE:  TEC Assessments are scientific opinions, provided solely for informational purposes. TEC Assessments should not be construed to suggest that the Blue Cross Blue Shield Association, Kaiser Permanente Medical Care Program or the TEC Program recommends, advocates, requires, encourages, or discourages any particular treatment, procedure, or service; any particular course of treatment, procedure, or service; or the payment or non-payment of the technology or technologies evaluated.