Acas Carotid Trial

The Asymptomatic Carotid Atherosclerosis (ACAS) and Asymptomatic Carotid Stenosis Trial (ACST) comparing BMM and CEA in asymptomatic patients suggested that an aggressive intervention with CEA produces more advantageous outcomes than BMM alone (Table 2). Carotid endarterectomy (CEA) for asymp­ tomatic carotid artery stenosis had not been proved/l.12 the Asymptomatic Ca­ rotid Atherosclerosis Study (ACAS) was initiated in 1987. The ACAS is an in­ vestigator-initiated randomized trial de­ signed to test whether CEA should be l. Component of management for selected. Purpose: Proponents of carotid angioplasty and stenting suggest that “high risk” patients, defined as patients excluded from the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and Asymptomatic Carotid Atherosclerosis Study (ACAS), may have a significantly higher risk of stroke with carotid endarterectomy (CEA).

Plain English Summary

Background and study aims
Carotid stenosis is a condition where one or both of the carotid arteries (the main blood vessels that supply the head and neck) become narrowed due to a build-up of fatty deposits (plaque). This increases the risk of having a stroke, when the blood supply to part of the brain is cut off. The aim of this study is to compare carotid surgery (carotid endarterectomy or CEA) with the best medical treatment (BMT) in patients with carotid stenosis but no symptoms. The aim of this study is to find out whether CEA and BMT together improve stroke-free survival time when compared to BMT alone. The study also aims to identify high-risk groups for whom the benefits of surgery and of BMT are increased and the long-term follow-up is looking at whether carotid endarterectomy reduces the risk of dementia in the long-term.
Who can participate?
Patients whose carotid stenosis has not caused symptoms for at least 6 months, and who have no past history of stroke
What does the study involve?
Participants are randomly allocated to be treated with either CEA plus BMT or BMT alone, unless symptoms develop requiring a CEA. Fatal and non-fatal stroke and death rates are compared between the two groups. For long-term follow-up the UK and Swedish participants' health records are also analysed for rates of stroke, death and dementia in the long-term. Relatives or friends of the UK participants are also asked to complete a postal questionnaire about the participant’s cognitive (mental) function.
What are the possible benefits and risks of participating?
There is no direct benefit to taking part but the information gained may help doctors to treat patients with asymptomatic carotid disease better in the future. There is no additional risk to taking part in this study. Long-term follow-up: there is no direct benefit to taking part but this follow-up may contribute to a wider benefit if carotid surgery is found to reduce the risk of developing later memory and thinking problems. The long-term follow-up does not involve any additional physical risk to the participants or does not provide any risk in relation to loss of anonymity.
Where is the study run from?
John Radcliffe Hospital (UK)
When is the study starting and how long is it expected to run for?
April 1993 to October 2019
Who is funding the study?
1. Medical Research Council (MRC) (UK)
2. Alzheimer’s Society (UK)
Who is the main contact?
Alison Halliday
acst@nds.ox.ac.uk

Trial website

Contact information

Type

Scientific

Primary contact

Prof Alison Halliday

ORCID ID

Contact details

ACST Trials Office
Level 6
West Wing
John Radcliffe Hospital
Headley Way
Oxford
OX3 9DU
United Kingdom
+44 (0)1865 617975
acst@nds.ox.ac.uk

Type

Public

Additional contact

Ms Mary Sneade

ORCID ID

Contact details

ACST trials office
Richard Doll Building
Old Road Campus
Roosevelt Drive
Oxford
OX3 7LF
United Kingdom
+44 (0)1865 617978
acst@nds.ox.ac.uk

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

G9408332

Study information

Scientific title

Asymptomatic Carotid Surgery Trial (ACST-1)

Acronym

ACST-1

Study hypothesis

The aim is to determine whether CEA and BMT improve stroke-free survival time when compared to BMT alone. The trial will also help identify high-risk groups in whom the benefits of surgery and of BMT would be increased.
Added 21/02/2017:
Primary objective: In participants with carotid stenosis, does carotid endarterectomy reduce the long-term risk of dementia, stroke or death related to carotid stenosis?
Secondary objective: In patients with carotid stenosis, does the long-term risk of dementia, stroke or death in recorded electronic records vary by duration of follow up, or participant characteristic recorded at baseline?
Updated 28/09/2018:
Primary objective: In participants with asymptomatic carotid stenosis, does carotid endarterectomy reduce the long-term risk of stroke, dementia or death, related to carotid stenosis?
Secondary objective: In patients with carotid stenosis, does the long-term risk of dementia or stroke in recorded electronic health records vary by duration of follow-up, or participant characteristic recorded at baseline?

Ethics approval

London Research Ethics Committee, 11/11/1998, ref: 98/2/92

Study design

Randomised controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use contact details to request a participant information sheet

Condition

Carotid stenosis

Intervention

CEA and best medical treatment (BMT) vs BMT alone
Added 19/08/2008: follow-up is a minimum of 5 years
Added 21/02/2017:
No further treatment interventions are planned as part of the long-term follow-up study.
Phase 1: Analysis of long-term data from UK and Swedish ACST-1 participant’s health records through electronic data linkage (NHS digital, UK; Socialstyrelsen, Sweden) for specific outcomes of incident stroke, death and dementia (16/SC/0406). The trialists will also be applying to the equivalent regulatory authorities in Scotland and Northern Ireland.
Phase 2: A relative or friend of the ACST-1 UK participants will be invited to complete a postal questionnaire (Informant Questionnaire on Cognitive decline in the Elderly-IQCODE) on the participant’s cognitive function.
Updated 28/09/2018:
No further treatment interventions are planned as part of the long-term follow-up study.
Phase 1: Phase 1: Analysis of long-term data from UK and Swedish ACST-1 participant’s health records through electronic data linkage (NHS digital, UK; Socialstyrelsen, Sweden) for specific outcomes of incident stroke and dementia (ethics approved 16/SC/0406).
Phase 2: A relative or friend of the ACST-1 UK participants will be invited to complete a postal questionnaire (short form of the validated ‘Informant Questionnaire on Cognitive decline in the Elderly’ - IQCODE) on the participant’s cognitive function.

Intervention type

Procedure/Surgery

Phase

Drug names

Primary outcome measure

Fatal and non-fatal stroke and death rates
Added 10/03/2017:
Long-term follow-up to determine specific outcomes of stroke and cognitive decline:
1. Long-term risk of dementia, stroke or death, measured using participant’s health records through electronic data linkage (NHS digital, UK; Socialstyrelsen, Sweden) at least 14 years post enrolment
2. Cognitive function, measured using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), MoCA and TICS-N, at least 14 years post enrolment
Updated 28/09/2018:
Long-term follow-up to determine specific outcomes of stroke and cognitive decline:
1. Long-term risk of dementia, stroke or death, measured using participant’s health records through electronic data linkage (NHS digital, UK; Socialstyrelsen, Sweden) at least 14 years post enrolment
2. Cognitive function, measured using the short form of the validated Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), at least 14 years post enrolment

Secondary outcome measures

Subsidiary analyses in an effort to identify high and low risk groups will include the effect of risk factors such as presence or absence of silent cerebral infarction on clinical outcome

Overall trial start date

01/04/1993

Overall trial end date

01/10/2019

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Patients whose carotid stenosis has not caused symptoms for at least 6 months
2. No past history of ipsilateral disabling or severe contralateral stroke
3. No clear indications or contraindications to carotid endarterectomy (CEA)

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

3120; 1601 for long-term follow-up

Participant exclusion criteria

1. Patients with a small likelihood of worthwhile benefit e.g. those with major life-threatening disease.
2. Patients who have had recent myocardial infarct, intracerebral neoplasia or aneurysm, or restenosis of an artery following previous CEA

Recruitment start date

19/04/1993

Recruitment end date

01/05/2003

Locations

Countries of recruitment

Austria, Belgium, Brazil, Bulgaria, Canada, Croatia, Cyprus, Czech Republic, Finland, France, Germany, Greece, Hungary, Ireland, Israel, Italy, Netherlands, New Zealand, Norway, Poland, Portugal, Russian Federation, Slovenia, Spain, Sweden, Switzerland, Tunisia, United Kingdom, United States of America

Trial participating centre

John Radcliffe Hospital
Oxford
OX3 9DU
United Kingdom

Trial participating centre

123 other centres
-
United Kingdom

Sponsor information

Organisation

Medical Research Council (MRC) (UK)

Sponsor details

20 Park Crescent
London
W1B 1AL
United Kingdom
+44 (0)20 7636 5422
clinical.trial@headoffice.mrc.ac.uk

Sponsor type

Research council

Website

Organisation

University of Oxford

Sponsor details

Research Services
Clinical Trials and Research Governance (CTRG)
Joint Research Office
1st Floor
Boundary Brook House
Churchill Drive
Headington
Oxford
OX3 7GB
United Kingdom
-
ctrg@admin.ox.ac.uk

Sponsor type

University/education

Website

Organisation

University of Oxford

Sponsor details

Sponsor type

Not defined

Website

Funders

Funder type

Research council

Funder name

Medical Research Council (MRC) (UK)

Alternative name(s)

MRC

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

United Kingdom

Funder name

Alzheimer's Society

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

Associations and societies (private and public)

Location

United Kingdom

Results and Publications

Publication and dissemination plan

The long-term follow-up results are anticipated to be presented at relevant scientific forums and conferences in the spring 2019 and published end of 2019 in peer-reviewed scientific journals.
IPD sharing plan
The datasets generated during and/or analysed during the current study are not expected to be made available.

Intention to publish date

31/10/2019

Participant level data

Not expected to be available

Basic results (scientific)

Publication list

2004 results in: http://www.ncbi.nlm.nih.gov/pubmed/15135594
2010 results in: http://www.ncbi.nlm.nih.gov/pubmed/20870099
2013 results in: http://www.ncbi.nlm.nih.gov/pubmed/23632980
2016 results in: http://www.ncbi.nlm.nih.gov/pubmed/27435205
2016 results in: http://www.ncbi.nlm.nih.gov/pubmed/27322379
2016 results in: http://www.ncbi.nlm.nih.gov/pubmed/27111809
2016 results in: http://www.ncbi.nlm.nih.gov/pubmed/26725253

Publication citations

Acas Carotid Trial Hearing

1. Results

   Halliday A, Mansfield A, Marro J, Peto C, Peto R, Potter J, Thomas D, , Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomised controlled trial., Lancet, 2004, 363, 9420, 1491-1502, doi: 10.1016/S0140-6736(04)16146-1.

2. Results

   Halliday A, Harrison M, Hayter E, Kong X, Mansfield A, Marro J, Pan H, Peto R, Potter J, Rahimi K, Rau A, Robertson S, Streifler J, Thomas D, , 10-year stroke prevention after successful carotid endarterectomy for asymptomatic stenosis (ACST-1): a multicentre randomised trial., Lancet, 2010, 376, 9746, 1074-1084, doi: 10.1016/S0140-6736(10)61197-X.

Additional files

Editorial Notes

• 6Population
• 8Outcomes

Clinical Question

Does carotid endarterectomy (CEA) and aggressive medical therapy reduce incidence of cerebral infarction over 5 years in patients with asymptomatic carotid artery stenosis?

Bottom Line

Patients with asymptomatic carotid artery stenosis of 60% or greater who are good surgical candidates have reduced 5-year risk of ipsilateral stroke.

Major Points

While the NASCET trial showed the benefit of CEA for patients symptomatic from carotid artery stenosis, the Asymptomatic Carotid Atherosclerosis Study (ACAS) trial sought to test whether a morbidity and mortality benefit existed for treated asymptomatic patients with CEA. ACAS demonstrated that asymptomatic patients with carotid artery stenosis >60% who undergo CEA have a lower chance of a combined endpoint of ipsilateral stroke, or perioperative stroke or death over 5 years.

Guidelines

No guidelines have been published that reflect the results of this trial.

Design

• 39 center trial
• Non-blinded
• Randomized
• N=1,662
  • Aggressive Medical Therapy alone (n=834)
  • Aggressive Medical Therapy + Carotid Endarterectomy (n=825)
• Enrollment: December 1987 to December 1993.
• Median follow-up: 2.7 years
• Analysis: Intention-to-treat

Population

Inclusion Criteria

• Aged 40-79
• Compatible history and findings on physical and neurological exams
• Performance of required lab and ECG testings no earlier than 3 months prior to randomization
• Patient accessibility and willingness to be followed for 5 years
• Valid informed consent

Exclusion Criteria

• Cerebrovascular events in the distribution of the study carotid artery
• Cerebrovascular events in the distribution of the vertebrobasilar arterial system
• Symptoms referable to the contralateral hemisphere within the previous 45 days
• Contraindications to aspirin
• Disorder that seriously complicate surgery
• Condition that would prevent continuing participation, or that would likely produce disability or death within 5 years)

Baseline Characteristics

• Gender: Approximately 2 Male:1 Female
• Age
  • 40-49: ~2%
  • 50-59: ~14%
  • 60-69: ~48%
  • 70-79: ~37%
• Percent Stenosis
  • 0-59%: NA
  • 60-69%: ~36%
  • 70-79%: ~37%
  • 80-80%: ~25%
  • 90-99%: ~5%

Acas Carotid Trial Meaning

Interventions

• 'Aggressive Medical Therapy': 325mg of regular or enteric-coated aspiring daily and 'modification of stroke risk factors'
• 'Aggressive Medical Therapy' Plus Carotid Endarterectomy

Outcomes

Comparisons are Medical versus Surgery

Primary Outcomes

Ipsilateral Stroke or any perioperative stroke or death

11.0% v 5.1% (p=0.004)

Secondary Outcomes

Major Ipsilateral Stroke or any perioperative major stroke or death

6.0% v 3.4% (p=0.12)

Ipsilateral TIA or Stroke or any perioperative TIA or stroke or death

19.2% v 8.2% (p<0.001)

Any stroke or any perioperative death)

17.5% v 12.4% (p=0.09)

Any major stroke or perioperative death

9.1% v 6.4% (p=0.26)

Any stroke or death

31.9% v 25.6% (p=0.08)

Any major stroke or death

25.5% v 20.7% (p=0.16)

Subgroup Analysis

Reduction due to Surgery in 5 year risk as a proportion of risk in the medical group

By Sex

Men: 0.66 (95% CI: 0.36 to 0.82)

Women: 0.17 (95% CI: -0.96 to 0.65)

By Age

< 68 y.o.: 0.60 (95% CI: 0.11 to 0.82)

>= 68 y.o.: 0.43 (95% CI: -0.07 to 0.70)

By history

Bilaterally asymptomatic: 0.46 (95% CI: 0.00 to 0.71)

Previous Contralateral endarterectomy or previous TIA or stroke: 0.65 (95% CI: 0.13 to 0.86)

Protocol adherence

Patients receiving assigned treatment: 0.55 (95% CI: 0.23 to 0.74)

Acas Carotid Trial

By degree of Stenosis

60-69.9%: 0.45 (95% CI: -0.70 to 0.82)

70-79.9%: 0.67 (95% CI: -0.65 to 0.94)

80-99.9%: 0.45 (95% CI: -2.19 to 0.91)

Criticisms

• This study relied heavily on composite endpoints for all endpoints, which may not be statistically rigorous.
• 'Aggressive Medical Therapy' in 1995 consisted on aspirin alone, whereas modern clinical guidelines demand treating patients with atherosclerotic disease with a statin. Additionally, modern medical therapy includes management of comorbidities such as hypertension and diabetes mellitus, but newer medications have improved efficacy, which may affect how effective medical management can be.

Funding

• This study was funded by the National Institutes of Neurological Disorders and Stroke, NIH.
• A conflict of interest may exist because the study was examining the clinical effectiveness of a surgical intervention by vascular surgeons, when these very physicians are those whose careers will suffer if CEA proved to be inferior.

Further Reading

Acas Carotid Trial Hearing