TEC Assessment Index

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

Assessment Program
Volume 22, No. 1
June 2007

Executive Summary

Background

Atherosclerotic lesions in the cervical carotid artery can result in luminal narrowing (stenosis) and increase the risk of disabling or fatal ischemic stroke—carotid endarterectomy (CEA) can diminish this risk. However, even in the best hands, the CEA is accompanied by periprocedural complications. Whether a patient ultimately accrues a net health benefit from CEA is based primarily on: magnitude of risk reduction accompanying CEA, periprocedural risk (stroke/death rate), expected event rate with best medical therapy alone, and the patient's anticipated life expectancy. Results from several large multicenter trials have established periprocedural stroke/death rates accompanied by a net health benefit and recommended life expectancy:

A potential alternative to CEA is carotid angioplasty and stenting (CAS) used with an embolic protection device (EPD)—particularly for patients with increased medical or anatomic risk. If CAS and CEA are equally safe and effective given similar patient characteristics and can be performed with periprocedural stroke/death rates accompanied by a net health benefit, then CAS is an alternative to CEA. CAS could also be superior to CEA, particularly under some conditions, such as inaccessible lesions or adverse anatomic conditions.

Objective

To review and evaluate available evidence concerning outcomes of CAS with EPD alone and compared to alternatives (CEA and best medical therapy) for reducing stroke risk in patients with carotid artery stenosis. The Assessment specifically seeks the following evidence:

1. Can CAS be performed with periprocedural stroke/death rates established as clinically acceptable and associated with an overall net health benefit among symptomatic and asymptomatic patients at: a) average medical and anatomic risk, b) increased medical risk, and c) increased anatomic risk?*

2. How do CAS, CEA, and best medical therapy compare in each of the above subgroups?

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 April 2007 and was limited to articles published in English that reported on human subjects.

Selection Criteria

Randomized, controlled trials and prospective registries with predefined endpoints and inclusion/exclusion criteria published in peer-reviewed journals.

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 average-risk symptomatic patients (≥50% and 60–99% 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 increased medical or anatomic risk—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 stroke/death rates with CAS in both trials exceeded those established as clinically acceptable and associated with an overall net health benefit in symptomatic patients: in SPACE, 7.7% (95% CI: 6.1–9.7); in EVA-3S, 9.6% (95% CI: 6.4–14.0).

SAPPHIRE found CAS noninferior to CEA for a composite primary endpoint of stroke, death or myocardial infarction (MI). 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 CAS and CEA patients, respectively, and exceeded the 3% stroke/death rate established as clinically acceptable and associated with an overall net health benefit in asymptomatic patients.

Publications from 7 registries and the lead-in phase of CREST (Carotid Revascularization Endarterectomy vs. Stent Trial) reported outcomes after CAS with EPD (6,712 patients). All enrolled symptomatic and asymptomatic patients. Six registries enrolled patients at increased risk. Three registries enrolling patients at increased medical or anatomic risk reported 30-day periprocedural complication rates according to the presence or absence of symptoms that exceeded those established as clinically acceptable and associated with an overall net health benefit following CEA:

A single registry reported a 3.9% periprocedural stroke/death/MI rate for patients with or without symptoms at increased anatomic risk. Interim results from the CREST lead-in phase enrolling average-risk patients reported 30-day stroke/death rates following CAS in symptomatic and asymptomatic patients of 5.7% and 3.7%, respectively.

The lack of outcomes clearly distinguished according to factors increasing medical risk or anatomic risk hinders interpreting the evidence—both from trials and registries. No studies comparing CAS to current best medical therapy were identified.

Author's Conclusions and Comments

Available evidence does not support concluding that CAS is performed with acceptable periprocedural stroke/death rates for symptomatic or asymptomatic patients, that it provides a net health benefit to patients at increased medical risk, or that it is equally effective as CEA. There is a clinical rationale and limited evidence suggesting CAS may be beneficial in the group of patients at increased anatomic risk; however, current evidence has not clearly differentiated outcomes for this subgroup according to symptomatic status.

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 or without distal embolic protection (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 or without 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. As of this writing, five manufacturers' stents 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 at increased risk for perioperative complications from CEA who are symptomatic with ≥50% stenosis or asymptomatic with >80% stenosis. CAS with these devices 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 stroke or death) following CAS in patients of average risk and increased medical risk. Periprocedural stroke/death rates surpassed those established as clinically acceptable and associated with an overall net health benefit following CEA. There is limited evidence and a clinical rationale to suggest CAS may be beneficial in the group of patients at increased anatomic risk, but present evidence has not clearly differentiated outcomes for this subgroup according to symptomatic status. Thus, there is insufficient evidence to draw conclusions regarding patients at increased anatomic risk.

A number of large ongoing trials will yield more evidence in the near future (e.g., "Carotid Revascularization Endarterectomy versus Stent Trial" [symptomatic and asymptomatic]; "International Carotid Stenting Study" [symptomatic]; and the "Asymptomatic Carotid Surgery Trial," ACT-1).

3. The technology must improve the net health outcome.

Available evidence does not support concluding that CAS with EPD improves the net health outcome among patients at average or increased medical risk. Evidence regarding patients at increased anatomic risk is suggestive of benefit, but insufficient to draw conclusions.

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

Available evidence does not support concluding that CAS with or without EPD is as beneficial as CEA for symptomatic patients at average risk or increased medical risk. Whether CAS with EPD is as beneficial as CEA for asymptomatic patients at average medical or anatomic risk cannot be determined because available evidence is insufficient to permit conclusions. There is no evidence comparing best medical therapy for symptomatic or asymptomatic patients at increased medical or anatomic risk, preventing conclusions.

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

Whether CAS with EPD improves health outcomes has not yet been demonstrated in the investigational setting.

Based on the above, use of carotid artery angioplasty and stenting with or without embolic protection of the cerebral circulation for patients with carotid artery stenosis does not meet the TEC criteria.

*There is theoretically a fourth group at increased anatomic and medical risk, but anatomic risk is presumed to be of greater clinical importance.

TEC Assessment Index

KEYWORDS: CardiovascularMedicine(category);SurgerySurgicalAlternatiesInterventionalRadiology (category);Acculink; Angioguard; angioplasty; antiplatelet; asymptomatic; atherosclerosis; attack; brain; cardiovascular; carotid; CAS; CEA; cerebral; cerebrovascular accident; cervical; clopidogrel; clot; CNS; CREST; CVA; death; DEP; distal; distal embolic protection; embolic; embolus; endarterectomy; EVA-3S; heart; high risk; ischaemic; ischemic; lumen; medical management; MI; morbidity; mortality; myocardial infarction; narrowing; periprocedural; perisurgical ; Precise; protection; registry; SAPPHIRE; SPACE; stenosis; stent; stenting; stroke; symptomatic ; thromboemboli; thromboembolism; TIA; transient; vascular;