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 relatively recently introduced procedure also used to treat carotid artery stenosis. 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 May 2010 and was limited to articles published in English that reported on human subjects. Additional focused searches were done in June 2010. Additionally, clinicaltrials.gov was searched with terms “carotid” and “angioplasty.”

Selection Criteria

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

Main Results

Five randomized, controlled trials compared CAS to CEA (with best medical therapy). The “Stent-Protected Angioplasty versus Carotid Endarterectomy” (SPACE), “Endarterectomy versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis” (EVA-3S), and “International Carotid Stenting Study” (ICSS) trials enrolled symptomatic patients. The “Carotid Revascularization Endarterectomy versus Stenting Trial” (CREST) enrolled both asymptomatic and symptomatic patients. The “Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy” (SAPPHIRE) trial enrolled symptomatic (≥50% stenosis) and asymptomatic (≥80% stenosis) patients with medical comorbidities or unfavorable anatomy.

Three trials enrolled only symptomatic patients not selected on the basis of medical comorbidities or unfavorable anatomy. SPACE and EVA-3S were terminated early: SPACE due to lack of funding and a larger-than-anticipated projected sample size and EVA-3S for reasons of safety and futility. Neither demonstrated noninferiority of CAS to CEA. While follow-up of ICSS participants is ongoing, targeted enrollment was met and interim safety results reported. Periprocedural death/stroke rates accompanying CAS in these 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 to 9.7); in EVA-3S 9.6% (95% CI: 6.4 to 14.0); in ICSS 7.1% (95% CI: 5.5 to 9.1).

CREST enrolled symptomatic and asymptomatic patients employing a primary endpoint of any periprocedural stroke, myocardial infarction (MI), or death or postprocedural ipsilateral stroke. With a median 2.5-year follow-up the estimated 4-year rates for the primary endpoint were 7.2% and 6.8% in the CAS and CEA arms respectively. Strokes were more frequent following CAS, while MI was more common after CEA. Thirty-day death/stroke rates were higher with CAS for both symptomatic patients (6.0% vs. 3.2%) and asymptomatic patients (2.5% vs. 1.4%).

The pooled periprocedural death/stroke rates for symptomatic patients undergoing CAS and CEA in the 4 trials (n=5,673) were 7.3% (95% CI: 6.1 to 8.6, I2=22%) and 4.2% (95% CI: 2.5 to 5.9, I2=68%); the pooled relative risk for periprocedural death/stroke with CAS compared to CEA was 1.75 (95% CI: 1.26 to 2.42, I2=40%).

SAPPHIRE concluded CAS to be noninferior to CEA for a composite primary endpoint of death, stroke, 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 (<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 9 registries, 30-day death/stroke rates were either reported or obtained from investigators; in the remaining 2 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 to 4.4, I2=57%); for symptomatic patients 7.4% (95% CI: 6.0 to 9.0, I2=59%). 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 Comment

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. In symptomatic patients not selected on the basis of medical comorbidities and/or unfavorable anatomy, results from 4 randomized, controlled trials provide strong evidence that CAS should not be performed. In the single trial (CREST) enrolling asymptomatic patients, 30-day death/stroke rates following CAS were higher than following CEA. Moreover, lacking comparison of intervention with current best medical therapies makes conclusions regarding any intervention in asymptomatic carotid artery disease questionable.

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. But 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.

Full Study

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

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