CREST

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Brott TG, et al. "Stenting versus Endarterectomy for Treatment of Carotid-Artery Stenosis". The New England Journal of Medicine. 2010. 363(1):11-23.
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Clinical Question

In patients with carotid artery stenosis, how does carotid artery stenting compare with carotid endarterectomy in terms of stroke, MI, and death?

Bottom Line

Among both symptomatic and asymptomatic patients with carotid stenosis, stenting and endarterectomy (CEA) were associated with similar rates of stroke, MI, and death, although stenting was associated with fewer periprocedural MIs and endarterectomy with fewer periprocedural strokes.

Major Points

The Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST) compared stenting to endarterectomy in the management of symptomatic and asymptomatic carotid artery stenosis. Prior studies demonstrated stenting as a valid alternative to CEA but yielded conflicting results, and a large-scale comparison study had not yet been done. CREST was the largest such comparative study, powered to more definitively answer the question of whether stenting or CEA should be the preferred revascularization strategy for patients with carotid stenosis.

CREST initially sought to enroll only symptomatic patients, but the eligibility criteria were amended in 2005 to allow asymptomatic patients with slightly different criteria for degree of stenosis. Ultimately the study enrolled 2,502 patients with carotid artery stenosis and randomized patients to either stenting or CEA. CREST demonstrated that stenting and CEA were similar in regards to the primary outcome of periprocedural stroke, MI, death, or ipsilateral stroke within 4 years. Secondary analyses revealed more periprocedural strokes with stenting (4.1% vs. 2.3%) but fewer periprocedural MIs (1.1% vs. 2.3%).

An additional secondary analysis demonstrated better outcomes with CEA among patients ≥70 years. A 2010 meta-analysis of the ICSS, EVA-3S, and SPACE trials corroborated this finding. It estimated that the risk of stroke or death was two-fold higher among patients ≥70 years when treated with stenting compared to CEA. Patients <70 years had similar risk of stroke or death regardless of revascularization strategy. This supports the notion that stenting favors younger patients, while CEA may be more suited for older patients.

Guidelines

The 2011 AHA/ACCF guidelines recommend stenting as a reasonable alternative to CEA among symptomatic patients with stenosis >70% and low risk of periprocedural complications (class I), recommending that CEA might be preferred among older patients or those with anatomy not amenable to stenting (class IIa). The guidelines suggest that prophylactic stenting for select asymptomatic patients with stenosis >70% by Doppler may be reasonable (class IIb).

Design

  • Multicenter, unblinded, parallel group, randomized, superiority trial
    • Randomization with stratification to center and asymptomatic vs. symptomatic
  • N=2,502 patients with carotid stenosis
    • Stenting (n=1,262)
    • CEA (n=1,240)
  • Setting: 117 centers in US and Canada
  • Analysis: Intention-to-treat
  • Enrollment: 2000-2008

Population

Inclusion Criteria

  • Symtomatic carotid artery stenosis with
    • ≥50% stenosis by angiography, or
    • ≥70% by ultrasound, or
    • ≥70% by CTA/MRA if ≥50% by ultrasound
  • Asymptomatic patients included in 2005 with
    • ≥60% stenosis by angiography, or
    • ≥70% by ultrasound, or
    • ≥80% by CTA/MRA if ≥50% by ultrasound
  • Symptoms defined as TIA, amaurosis fugax, or minor nondisabling stroke in carotid territory within prior 180 days

Exclusion Criteria

  • Prior severe stroke
  • Chronic AF or paroxysmal AF in prior 6 months
  • AF requiring anticoagulation
  • ACS in prior 30 days
  • Clinical and anatomic suitability for either technique

Baseline Characteristics

From the stenting group.

  • Demographics: Age 69 years, male 64%, Caucasian 93%
  • Risk factors: HTN 86%, DM 31%, HLD 83%, smoker 26%, CVD 42%
  • PSH: CABG 20%
  • Baseline health data: SBP 142 mmHg, DBP 74 mmHg
  • Left carotid artery: 51%
  • Asymptomatic: 47%
  • Contralateral occlusion: 2.7%
  • Time until treatment from randomization: 6 days (interquartile range of 9 days)
  • Stenting group-specific:
    • Length of lesion: 17.8 mm
    • Length of stent: 34.4
    • Balloon angioplasty before stent: 68%
    • Embolic protection: 96%
    • Antiplatelets 48 hours before procedure: 98%
    • Procedure with heparin: 86%
    • Procedure with bivalirudin: 14%
    • Procedure with vasopressors: 30%
    • Post-procedure with antiplatelets: 99%
    • At least four weeks post-procedure with aspirin with clopidogrel or ticlopidine: 88%
  • CEA-specific:
    • General anesthesia: 90%
    • Patch technique: 62%
    • Shunt technique: 57%
    • Aspirin 48 hours before procedure: 92%
    • Procedure with vasopressors: 61%
    • Post-prcedure with antiplatelet therapy: 91%

Interventions

Procedures

  • Both groups received standard of care medical therapy (eg, for HTN, HLD)
  • Stenting used the RX Acculink stent ± RX Accunet embolism-protection device
  • Prior to stenting, patients were given aspirin and clopidogrel
    • Aspirin 325mg PO BID and clopidogrel 75mg PO BID at least 48 hours before
    • Aspirin 650mg PO once and clopidogrel 450mg PO once at least 4 hours before procedure if not on already
  • Following stenting:
    • Aspirin 325mg PO qday or BID for 30 days with clopidogrel75mg PO daily or ticlopidine250 mg PO BID for four weeks
    • Some form of antiplatelet therapy was encouraged for all patients beyond this point
  • Prior to and following CEA, patients received aspirin 325mg PO daily
    • Alternative therapies: ticlopidine 250mg PO BID, clopidogrel 75mg PO daily, aspirin 81mg PO daily, aspirin with extended-release dipyridamole PO BID

Follow Up

  • Neurologic assessments: prior to intervention, 18 and 54 hours after intervention, 1 month, and every 6 months thereafter
    • National Institutes of Health Stroke Scale (NIHSS): from 0 (without deficits) to 42 (coma/quadreplegia)
    • Modified Rankin scale: from 0 (without deficits) to 6 (death)
    • TIA-Stroke Questionnaire: Evaluates presence of TIA or stroke
  • Cardiac workup:
    • Cardiac enzymes: prior to intervention and 6-8 hours after
    • EKG: prior to intervention, 6-48 hours after, and 1 month after
    • Carotid ultrasound: prior to intervention, 1 month, 6 months, and 1 year after
  • Other:
    • Phone interview (including TIA-Stroke Questionnaire): 3 months, 6 months, and each 6 months after
    • General health status: assessed at baseline, 2 weeks, 1 month, and 1 year
    • Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36): From 0 (bad health) to 100 (great health), also evaluates physical & mental health

Outcomes

Comparisons are stenting vs. CEA.

Primary Outcome

Composite (any stroke, MI, or death periprocedurally or ipsilateral stroke within 4 years)
Periprocedurally: 5.2% vs. 4.5% (HR 1.18; 95% CI 0.82-1.68; P=0.38)
Four year follow up: 7.2% vs. 6.8% (HR 1.11; 95% CI 0.81-1.51; P=0.51)

Secondary Outcomes

Death
Periprocedurally: 0.7% vs. 0.3% (HR 2.25; 95% CI 0.69-7.30; P=0.18)
Four year follow up: 10.2% vs. 12.6% (HR 1.12; 95% CI 0.83-1.51; P=0.45)
Any stroke
Periprocedurally: 4.1% vs. 2.3% (HR 1.79; 95% CI 1.14-2.82; P=0.01)
Four year follow up: 10.2% vs. 7.9% (HR 1.40; 95% CI 1.03 to 1.89; P=0.03)
Major ipsilateral stroke
Periprocedurally: 0.9% vs. 0.3% (HR 2.67; 95% CI 0.87-8.40; P=0.09)
Four year follow up: 1.4% vs. 0.5% (HR 2.56; 95% CI 1.00-6.54; P=0.05)
Major non-ipsilateral stroke
Periprocedurally: 0% vs. 0.3% (no analysis provided)
Four year follow up: 0.9% vs. 0.8%; 95% CI 0.73; P=0.56)
Minor ipsilateral stroke
Periprocedurally: 2.9% vs. 1.4% (HR 2.16; 95% CI 1.22-3.83; P=0.009)
Four year follow up: 4.5% vs. 3.5% (HR 1.43; 95% CI 0.94-2.19; P=0.10)
Minor non-ipsilateral
Periprocedurally: 0.3% vs. 0.3% (HR 1.02; 95% CI 0.25-4.07; P=0.99)
Four year follow up: 4.0% vs. 3.8% (HR 1.11; 95% CI 0.67-1.82; P=0.69)
MI
More common with CEA periprocedurally but no difference at 4 years.
Periprocedurally: 1.1% vs. 2.3% (HR 0.50; 95% CI 0.26-0.94; P=0.03)
Four year follow up: 4.0% vs. 3.8% (HR 1.11; 95% CI 0.67-1.82; P=0.69)
Periprocedural stroke or ipsilateral postprocedural stroke
Periprocedurally: 4.4% vs. 2.3% (HR 1.79; 95% CI 1.14-2.82; P=0.01)
Four year follow up: 6.2% vs. 4.7% (HR 1.44; 95% CI 1.00-2.06; P=0.049)
Major stroke
Periprocedurally: 0.9% vs. 0.6% (HR 1.35; 95% CI 0.54-3.36; P=0.52)
Four year follow up: 1.4% vs. 0.8% (HR 1.55; 95% CI 0.70-3.42; P=0.28)
Minor stroke
More common with stenting periprocedurally but no difference at 4 years.
Periprocedurally: 3.2% vs. 1.7% (HR 1.95; 95% CI 1.15-3.30; P=0.01)
Four year follow up: 4.8% vs. 3.8% (HR 1.39; 95% CI 0.93-2.09; P=0.11)
Perioprocedural stroke, ipsilateral postprocedural stroke, or death
Periprocedurally: 4.4% vs. 2.3% (HR 1.90; 95% CI 1.21-2.98, P=0.005)
Four year follow up: 6.4% vs. 4.7% (HR 1.50; 95% CI 1.05-2.15; P=0.03)

Subgroup Analysis

Age and the primary endpoint
Stenting better if age <70 years, CEA better if age ≥70 years (P=0.02)

Adverse Events

Cranial nerve palsies
Periprocedurally: 0.3% vs. 4.7% (HR 0.07; 95% CI 0.02-0.18; P not defined)

Criticisms

  • Credentialing of those performing the interventions was higher than in real practice. As such, lower complication rates were demonstrated in this study than in similar studies without as strict credentialing -- thereby limiting generalizability
  • Only a single stenting technology was used
  • Lack of comparison to medical therapy
  • Lack of blinding
  • No explicit analysis of quality of life in those affected by stroke and those affected by MI hinders generalizability of the outcomes
  • The authors screened for asymptomatic MI but not CVA
  • Use of dual platelet therapy with stenting and single platelet therapy in CEA couple potentially have skewed results
  • A third arm with modern medical therapy alone would have helped guide outcomes

Funding

  • National Institute of Neurological Disorders and Stroke at the National Institutes of Health
  • Abbot Vascular Solutions provided funding and donated their CEA systems
  • Authors with multiple conflicts

Further Reading