ACST-1

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Halliday A, et al. "10-year stroke prevention after successful carotid endarterectomy for asymptomatic stenosis (ACST-1): a multicentre randomised trial". The Lancet. 2010. 376(9746):1074-1084.
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Clinical Question

In patients with asymptomatic significant carotid artery stenosis (≥60%), does immediate carotid endarterectomy (CEA) reduce the stroke risk as compared to deferral of CEA?

Bottom Line

In asymptomatic patients <75 years of age with asymptomatic significant carotid artery stenosis (≥60%), successful immediate CEA reduces 10-year risk of stroke without a significant increase in peri-operative mortality and morbidity as compared to deferred CEA.

Major Points

The stroke prevention after successful carotid endarterectomy for asymptomatic stenosis (ACST-1) randomized 3,120 patients to assess the effect of immediate CEA on stroke risk as compared to deferred CEA.

In asymptomatic patients <75 years of age with asymptomatic significant carotid artery stenosis (≥60%), successful immediate CEA reduces 10-year risk of stroke without a significant increase in peri-operative mortality and morbidity as compared to deferred CEA.

Another study on asymptomatic patients with carotid stenosis is the Asymptomatic Carotid Atherosclerosis Study (ACAS).[1] In addition, the Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST) trial enrolled both symptomatic and asymptomatic patients.[2]

Guidelines

2011 ASA/ACCF/AHA Guideline on the Management of Patients With Extracranial Carotid and Vertebral Artery Disease[3]

  • Selection of asymptomatic patients for carotid revascularization should be guided by an assessment of comorbid conditions, life expectancy, and other individual factors and should include a thorough discussion of the risks and benefits of the procedure with an understanding of patient preferences. (Class I; Level of Evidence: C)
  • It is reasonable to perform CEA in asymptomatic patients who have more than 70% stenosis of the internal carotid artery if the risk of perioperative stroke, MI, and death is low. (Class IIa; Level of Evidence: A)
  • In symptomatic or asymptomatic patients at high risk of complications for carotid revascularization by either CEA or CAS because of comorbidities, the effectiveness of revascularization versus medical therapy alone is not well established. (Class IIb; Level of Evidence: B)

Design

  • Multicenter, blinded, randomized, controlled trial
  • N=3,120
    • immediate CEA (n=1,560)
    • deferral of any carotid procedure (n=1,560)
  • Setting: 126 centers in 30 countries
  • Enrollment: April 1993 to July 2003
  • Median follow-up: 9 years
  • Analysis: Intention-to-treat
  • Primary outcome:
    • peri-operative mortality and morbidity (death or stroke within 30 days)
    • non-perioperative stroke

Population

Inclusion Criteria

  • severe unilateral or bilateral carotid artery stenosis (no fixed cut-off but generally ≥60%)
  • this stenosis had not caused stroke, transient cerebral ischemia, or any other relevant neurological symptoms in the past 6 months
  • fit for surgery, if required
  • no circumstance or condition precluded long-term follow-up
  • doctor and patient were both substantially uncertain whether to choose immediate CEA or deferral of CEA.

Exclusion Criteria

These reasons are specified by the physician, not by the protocol

  • a small likelihood of benefit:
    • a carotid plaque not causing significant stenosis and confers a low risk of stroke
    • patients with major life-threatening co-morbidities other than stroke
  • poor CEA risk such as recent acute myocardial infarction and intra-cerebral tumors or aneurysm.
  • re-stenosis following previous CEA
  • emboli is likely to be from a cardiac source

Baseline Characteristics

This describes all randomized patients. There was no significant difference in baseline characteristics between the immediate and deferred CEA patients.

  • Mean age (years): 68 (40-91)
  • Male gender (%): 65.5
  • Hypertension (%): 65
  • Mean systolic blood pressure (mmHg): 153
  • Diabetes (%): 20
  • Mean cholesterol (mmol/L): 5.8
  • Previous contralateral CEA (%): 24

Interventions

  • Doppler ultrasound was used to assess carotid artery stenosis. Generally, the criteria was defined according to the NASCET trial.
  • All patients received therapy targeting risk factors for stroke and death including smoking, hypertension, diabetes mellitus, obesity, hyperlipidemia, polycythemia and ischemic heart disease
  • Anti-platelet therapy was prescribed to majority of the patients unless there was a specific contraindication or the patient was already on anticoagulant therapy

Immediate CEA

  • Procedure carried out as soon as possible using the surgeon's preferable technique
  • 50% of patients underwent ipsilateral surgery by 1 month, 89.3% by 1 year after randomisation and 91·8% by 5 years after randomisation
  • Shunting during surgery for maintaining cerebral perfusion was optional
  • Antiplatelet therapy was generally prescribed for post-operative treatment

Deferral of CEA

  • not to undergo CEA unless they develop symptoms suggestive of carotid artery ischemia or other definite indication for surgery was thought to have arisen
  • 26% of patients in this group had CEA within 10 years

Outcomes

Comparisons are immediate CEA vs. deferred CEA

Primary Outcomes

peri-operative mortality and morbidity (death or stroke within 30 days) at 5-years[4]

data expressed as % of total CEA

2.8% (2·0-3·9) vs. 4.5% (2·2-8·0) (P=NS)

overall the risk per CEA was 3·1% (95% CI 2·3-4·1)

peri-operative mortality and morbidity (death or stroke within 30 days) at 10-years

data expressed as % of total CEA

2.9% (2.1-3.8) vs. 3.6% (2.2-5.7) (P=NS)

overall the risk per CEA was 3·0% (95% CI 2·4-3.9)

non-perioperative stroke risk at 5-years

data expressed as events/person-years

4·1% vs. 10·0% (gain 5·9%; 95% CI 4·0-7·8; P<0.0001)

non-perioperative stroke risk at 10-years

data expressed as events/person-years

10·8% vs. 16·9% at (gain 6·1%; 95% CI 2·7-9·4; P=0.0004)

Secondary outcomes

Any stroke or perioperative death at 5 years

data expressed as events/CEA+other events

6·9% vs. 10·9% (gain 4·1%, 95% CI 2·0-6·2; P=0.0001)

Any stroke or perioperative death at 10 years

data expressed as events/CEA+other events

13·4% vs. 17·9% (gain 4·6%, 95% CI 1·2-7·9; P=0.009)

Subgroup Analysis

  • At 10-years, the benefits of CEA was not significant for both men and for women ≥75 years old at entry to trial
  • At 10-years, there was no significant heterogeneity between benefits in subgroups of gender, pre-randomisation cholesterol, pre-randomisation systolic blood pressure, severity of stenosis, diabetes mellitus, IHD, use of anti-hypertensive, anti-thrombotic or lipid-lowering agents at entry.
  • At 10-years, there was no significant heterogeneity between perioperative hazards in subgroups of age, gender or severity of stenosis.
  • However subgroup analyses are not definitive due to the small number of events in the trial.

Criticisms

  • Uncertainty if patients achieved ideal blood pressure levels (<140/90 mm Hg) or LDL-C (<2·4 mmol/L) as recommended by JNC 7 and NCEP III guidelines. This affects their absolute risk for stroke.[5]
  • Lipid-lowering therapy may have been suboptimal in the trial.[6]
  • Ultrasound was used in the trial, which may be associated with its own imperfections as compared to modern imaging techniques, such as angiography.[7]
  • Contemporary medical therapy has changed since the trial. Patients in the ACST did not receive best medical therapy as compared to modern practice.[8]
  • Medical therapy was not standardized and left to the discretion of clinicians.[8]
  • Surgeons in the trial were highly selected. It's important to consider if a comparable incidence of operative complications can be achieved in local centres.[7]
  • It is unclear if females obtain as much benefit as males from CEA.[3][9]

Funding

UK Medical Research Council, BUPA Foundation, Stroke Association

Further Reading

  1. Endarterectomy for asymptomatic carotid artery stenosis. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. JAMA. 1995. 10;273(18):1421–8.
  2. Brott TG, Hobson RW, Howard G, et al. Stenting versus Endarterectomy for Treatment of Carotid-Artery Stenosis. New England Journal of Medicine. 2010. 1;363(1):11–23.
  3. 3.0 3.1 Brott TG, Halperin JL, Abbara S, Bacharach JM, Barr JD, Bush RL, et al. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS Guideline on the Management of Patients With Extracranial Carotid and Vertebral Artery Disease. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery Developed in Collaboration With the American Academy of Neurology and Society of Cardiovascular Computed Tomography. J Am Coll Cardiol. 2011;57(8):e16–94.
  4. Halliday A, Mansfield A, Marro J, et al. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomised controlled trial. Lancet. 2004;363:1491–1502
  5. Amarenco P, Labreuche J, Mazighi M. Lessons from carotid endarterectomy and stenting trials. Lancet. 2010;376(9746):1028-31
  6. Paraskevas KI, Mikhailidis DP, Veith FJ. Best medical treatment for a symptomatic carotid artery stenosis. Lancet. 2011;377(9760):123; author reply 123-4
  7. 7.0 7.1 Barnett HJ. Carotid endarterectomy. Lancet. 2004;364(9440):1122-3; author reply 1125-6.
  8. 8.0 8.1 Jonas DE, Feltner C, Amick HR, Sheridan S, Zheng ZJ, Watford DJ, et al. Screening for Asymptomatic Carotid Artery Stenosis: A Systematic Review and Meta-Analysis for the U.S. Preventive Services Task Force. Evidence Synthesis No. 111. AHRQ Publication No. 13-05178-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2014
  9. Rothwell PM. ACST: which subgroups will benefit most from carotid endarterectomy? Lancet. 2004;364(9440):1122-3; author reply 1125-6