Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial

Carotid Stenosis Clinical Trial

— CREST-2  

Official title:

Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02089217
• Other study ID #: 13-004051
• Secondary ID: U01NS080168
• Status: Recruiting
• Phase: N/A
• Start date: December 9, 2014
• Est. completion date: February 2026

Study information

• Verified date: January 2024
• Source: Mayo Clinic
• Contact: CREST-2 Administrative Center
• Phone: 844-956-1826
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Carotid revascularization for primary prevention of stroke (CREST-2) is two independent multicenter, randomized controlled trials of carotid revascularization and intensive medical management versus medical management alone in patients with asymptomatic high-grade carotid stenosis. One trial will randomize patients in a 1:1 ratio to endarterectomy versus no endarterectomy and another will randomize patients in a 1:1 ratio to carotid stenting with embolic protection versus no stenting. Medical management will be uniform for all randomized treatment groups and will be centrally directed.

Description:

Prevention of stroke involves managing and treating risk factors. Most strokes are caused when blood flow to a portion of the brain is blocked. One place this often happens is in the carotid artery. This blockage is called atherosclerosis or hardening of the arteries.

The purpose of this trial is to determine the best way to prevent strokes in people who have a high amount of blockage of their carotid artery but no stroke symptoms related to that blockage. Each eligible participant will be evaluated to determine which procedure(s) is best for him/her. All participants will receive intensive medical treatment. In addition, participants will be randomized to receive the selected procedure or not.

The trial will be conducted in the United States and Canada by physicians carefully selected on their ability to perform the procedures at low risk. Another key component of the trial is that important stroke risk factors, including hypertension, diabetes, high cholesterol, cigarette smoking, physical activity, and diet will be managed intensively. Participants will remain in the study for 4 years.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 2480
• Est. completion date: February 2026
• Est. primary completion date: February 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 35 Years to 100 Years

Eligibility

General Inclusion Criteria

1. Patients =35 years old.

2. Carotid stenosis defined as:

• Stenosis =70% by catheter angiography (NASCET Criteria); OR

• by DUS with =70% stenosis defined by a peak systolic velocity of at least 230 cm/s plus at least one of the following:

1. an end diastolic velocity =100 cm/s, or

2. internal carotid/common carotid artery peak systolic velocity ratio =4.0, or

3. CTA with = 70% stenosis, or

4. MRA with = 70% stenosis.

3. No medical history of stroke or TIA ipsilateral to the stenosis within 180 days of randomization. Life-long asymptomatic patients will be defined as having no medical history of stroke or transient ischemic attack and negative responses to all of the symptom items on the Questionnaire for Verifying Stroke-free Status (QVSS).18

4. Patients must have a modified Rankin Scale score of 0 or 1 at the time of informed consent.

5. Women must not be of childbearing potential or, if of childbearing potential, have a negative pregnancy test prior to randomization.

6. Patients must agree to comply with all protocol-specified follow-up appointments.

7. Patients must sign a consent form that has been approved by the local governing Institutional Review Board (IRB)/Medical Ethics Committee (MEC) of the respective clinical site.

8. Randomization to treatment group will apply to only one carotid artery for patients with bilateral carotid stenosis. Management of the non-randomized stenosis may be done in accordance with local PI recommendation. Treatment of the non-study internal carotid artery must take place at least 30 days prior to randomization, or greater than 44 days after randomization and 30 days after the study procedure is completed (whichever is longer).

9. Carotid stenosis must be treatable with CEA, CAS, or either procedure.

General Exclusion Criteria

1. Intolerance or allergic reaction to a study medication without a suitable management alternative.

2. GI hemorrhage within 1 month prior to enrollment that would preclude antiplatelet therapy.

3. Prior major ipsilateral stroke in the past with substantial residual disability (mRS = 2) that is likely to confound study outcomes.

4. Severe dementia.

5. History of major symptomatic intracranial hemorrhage within 12 months that was not related to anticoagulation.

6. Prior Intracranial hemorrhage that the investigator believes represents a contraindication to the perioperative or periprocedural antithrombotic and antiplatelet treatments necessary to complete endarterectomy or stenting per protocol.

7. Current neurologic illness characterized by fleeting or fixed neurologic deficits that cannot be distinguished from TIA or stroke.

8. Patient objects to future blood transfusions.

9. Platelet count <100,000/microliter or history of heparin-induced thrombocytopenia.

10. Anticoagulation with Phenprocoumon (Marcumar®), warfarin, or a direct thrombin inhibitor, or anti-Xa agents.

11. Chronic atrial fibrillation.

12. Any episode of atrial fibrillation within the past 6 months or history of paroxysmal atrial fibrillation that is deemed to require chronic anticoagulation.

13. Other high-risk cardiac sources of emboli, including left ventricular aneurysm, severe cardiomyopathy, aortic or mitral mechanical heart valve, severe calcific aortic stenosis (valve area < 1.0 cm2), endocarditis, moderate to severe mitral stenosis, left atrial thrombus, or any intracardiac mass, or known unrepaired PFO with prior paradoxical embolism.

14. Unstable angina defined as rest angina with ECG changes that is not amenable to revascularization (patients should undergo planned coronary revascularization at least 30 days before randomization).

15. Left Ventricular Ejection fraction <30% or admission for heart failure in prior 6 months.

16. Respiratory insufficiency with life expectancy < 4 years or FEV1 <30% of predicted value.

17. Known malignancy other than basal cell non-melanoma skin cancer. There are two exceptions to this rule: patients with prior cancer treatment and no recurrence for >5 years are eligible for enrollment and cancer patients with life expectancy of greater than 5 years are eligible for enrollment.

18. Any major surgery, major trauma, revascularization procedure, or acute coronary syndrome within the past 1 month.

19. Either the serum creatinine is = 2.5 mg/dl or the estimated GFR is < 30 cc/min.

20. Major (non-carotid) surgery/procedures planned within 3 months after enrollment.

21. Currently listed or being evaluated for major organ transplantation (i.e. heart, lung, liver, kidney).

22. Actively participating in another drug or aortic arch or cerebrovascular device trial for which participation in CREST-2 would be compromised with regard to follow-up assessment of outcomes or continuation in CREST-2.

23. Inability to understand and cooperate with study procedures or provide informed consent.

24. Non-atherosclerotic carotid stenosis (dissection, fibromuscular dysplasia, or stenosis following radiation therapy).

25. Previous ipsilateral CEA or CAS.

26. Ipsilateral internal or common carotid artery occlusion.

27. Intra-carotid floating thrombus.

28. Ipsilateral intracranial aneurysm > 5 mm.

29. Extreme morbid obesity that would compromise patient safety during the procedure or would compromise patient safety during the periprocedural period.

30. Coronary artery disease with two or more proximal or major diseased coronary arteries with 70% stenosis that have not, or cannot, be revascularized.

Specific carotid endarterectomy exclusion criteria

Patients who are being considered for revascularization by CEA must not have any of the following criteria:

1. Serious adverse reaction to anesthesia not able to be overcome by pre-medication.

2. Distal/intracranial stenosis greater than index lesion.

3. Any of the following anatomical: radical neck dissection; surgically inaccessible lesions (e.g. above cervical spine level 2 (C2)); adverse neck anatomy that limits surgical exposure (e.g. spinal immobility - inability to flex neck beyond neutral or kyphotic deformity, or short obese neck); presence of tracheostomy stoma; laryngeal nerve palsy contralateral to target vessel; or previous extracranial-intracranial or subclavian bypass procedure ipsilateral to the target vessel.

Specific Carotid Artery Stenting Exclusion Criteria

Patients who are being considered for revascularization by CAS must not have any of the following criteria:

1. Allergy to intravascular contrast dye not amenable to pre-medication.

2. Type III, aortic arch anatomy.

3. Angulation or tortuosity (= 90 degree) of the innominate and common carotid artery that precludes safe, expeditious sheath placement or that will transmit a severe loop to the internal carotid after sheath placement.

4. Severe angulation or tortuosity of the internal carotid artery (including calyceal origin from the carotid bifurcation) that precludes safe deployment of embolic protection device or stent. Severe tortuosity is defined as 2 or more = 90 degree angles within 4 cm of the target stenosis.

5. Proximal/ostial CCA, innominate stenosis or distal/intracranial stenosis greater than index lesion.

Excessive circumferential calcification of the stenotic lesion defined as >3mm thickness of calcification seen in orthogonal views on fluoroscopy.(Note: Anatomic considerations such as tortuosity, arch anatomy, and calcification must be evaluated even more carefully in elderly subjects (= 70 years).)

6. Target ICA vessel reference diameter <4.0 mm or >9.0 mm. Target ICA measurements may be made from angiography of the contralateral artery. The reference diameter must be appropriate for the devices to be used.

7. Inability to deploy or utilize an FDA-approved Embolic Protection Device (EPD).

8. Non-contiguous lesions and long lesions (>3 cm).

9. Qualitative characteristics of stenosis and stenosis-length of the carotid bifurcation (common carotid) and/or ipsilateral external carotid artery, that preclude safe sheath placement.

10. Occlusive or critical ilio-femoral disease including severe tortuosity or stenosis that necessitates additional endovascular procedures to facilitate access to the aortic arch or that prevents safe and expeditious femoral access to the aortic arch. "String sign" of the ipsilateral common or internal carotid artery.

11. Angiographic, CT, MR or ultrasound evidence of severe atherosclerosis of the aortic arch or origin of the innominate or common carotid arteries that would preclude safe passage of the sheath and other endovascular devices to the target artery as needed for carotid stenting.

Related Conditions & MeSH terms

• Carotid Stenosis
• Constriction, Pathologic

Intervention

Procedure:
• Carotid endarterectomy (CEA)
Carotid endarterectomy

Device:
• Carotid Stenting (CAS)
Carotid stenting

Other:
• Intensive Medical Management - no CEA
Intensive Medical Management alone - no CEA
• Intensive Medical Management - no CAS
Intensive Medical Management alone - no CAS

Locations

Country	Name	City	State
Australia	Fiona Stanley Hospital	Perth
Canada	Nova Scotia Health Authority	Halifax	Nova Scotia
Canada	CHU de Québec/ Hôpital de l'Enfant-Jésus	Québec City	Quebec
Canada	St. Michael's Hospital	Toronto	Ontario
Canada	Vancouver General Hospital	Vancouver	British Columbia
Canada	St. Boniface Hospital	Winnipeg	Ontario
Israel	Soroka University Medical Center	Be'er Sheva
Israel	Soroka University Vascular Surgery	Be'er Sheva
Israel	Rambam Healthcare	Haifa
Israel	Shaare-Zedek Medical Center	Jerusalem
Israel	Rabin Medical Center	Petach Tikva
Spain	Hospital Clinic Barcelona	Barcelona
United States	Lehigh Valley Hospital - Network Office of Research	Allentown	Pennsylvania
United States	UPMC Altoona	Altoona	Pennsylvania
United States	University of Michigan Hospital and Health Systems	Ann Arbor	Michigan
United States	VA Ann Arbor Healthcare System	Ann Arbor	Michigan
United States	Atlanta VA Medical Center	Atlanta	Georgia
United States	Emory University	Atlanta	Georgia
United States	Cardiothoracic and Vascular Surgeons	Austin	Texas
United States	Seton Medical Center Austin	Austin	Texas
United States	John Hopkins Medical Institution	Baltimore	Maryland
United States	University of Maryland VA	Baltimore	Maryland
United States	Overlake Hospital Medical Center	Bellevue	Washington
United States	Brookwood Medical Center	Birmingham	Alabama
United States	The University of Alabama at Birmingham	Birmingham	Alabama
United States	Beth Israel Deaconess Medical Center (BIDMC)	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	St. Elizabeth's Medical Center	Boston	Massachusetts
United States	SUNY Buffalo	Buffalo	New York
United States	Cooper University	Camden	New Jersey
United States	Southern Illinois Healthcare	Carbondale	Illinois
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University of Virginia Health System	Charlottesville	Virginia
United States	The University of Chicago Medical Center	Chicago	Illinois
United States	University of Cincinnati Medical Center	Cincinnati	Ohio
United States	Morton Plant Hospital	Clearwater	Florida
United States	Louis Stokes Cleveland VA Medical Center	Cleveland	Ohio
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	Ohio State Medical Center	Columbia	Ohio
United States	OhioHealth Research Institute	Columbus	Ohio
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Henry Ford Health System	Detroit	Michigan
United States	Doylestown Hospital	Doylestown	Pennsylvania
United States	Duke University Medical Center	Durham	North Carolina
United States	UPMC Hamot	Erie	Pennsylvania
United States	Northshore University	Evanston	Illinois
United States	Northwestern University	Evanston	Illinois
United States	Inova Fairfax Health Care	Falls Church	Virginia
United States	Michigan Vascular Center/McLaren- Flint	Flint	Michigan
United States	Mission Cardiovascular Research	Fremont	California
United States	University of Florida Health at Shands	Gainesville	Florida
United States	Minneapolis Clinic of Neurology, Ltd./ North Memorial Medical Center	Golden Valley	Minnesota
United States	St. Mary's Medical Center	Grand Junction	Colorado
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Valley Baptist Medical Center	Harlingen	Texas
United States	Hartford Hospital	Hartford	Connecticut
United States	PennState Health Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Houston Methodist Hospital	Houston	Texas
United States	Memorial Hermann Texas Medical Center	Houston	Texas
United States	Huntsville Hospital/ Heart Center Research Alabama	Huntsville	Alabama
United States	Franciscan St. Francis Health	Indianapolis	Indiana
United States	University of Iowa	Iowa City	Iowa
United States	First Coast Cardiovascular Institute	Jacksonville	Florida
United States	Lyerly Neurosurgery	Jacksonville	Florida
United States	Mayo Clinic	Jacksonville	Florida
United States	UF Jacksonville	Jacksonville	Florida
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	CVA Heart Institute	Kingsport	Tennessee
United States	Tennova Healthcare/ Turkey Creek Medical Center	Knoxville	Tennessee
United States	Gundersen Clinic, Ltd	La Crosse	Wisconsin
United States	UC San Diego Health	La Jolla	California
United States	Sparrow Clinical Research Institute	Lansing	Michigan
United States	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire
United States	Baptist Health Lexington	Lexington	Kentucky
United States	University of Kentucky Hospital	Lexington	Kentucky
United States	Central Arkansas Veteran's Healthcare System	Little Rock	Arkansas
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Kaiser Permanente Los Angeles	Los Angeles	California
United States	Keck Medical Center of University of Southern California	Los Angeles	California
United States	University of California Los Angeles (UCLA)	Los Angeles	California
United States	University of Louisville	Louisville	Kentucky
United States	Medical Center of the Rockies	Loveland	Colorado
United States	University of Wisconsin	Madison	Wisconsin
United States	The Feinstein Institute of Medical Research	Manhasset	New York
United States	Loyola University Medical Center	Maywood	Illinois
United States	Baptist Memorial Hospital	Memphis	Tennessee
United States	Miami Cardiac and Vascular Institute at Baptist Hospital of Miami	Miami	Florida
United States	University of Miami Hospital	Miami	Florida
United States	Mount Sinai Medical Center of Florida	Miami Beach	Florida
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	University of Minnesota	Minneapolis	Minnesota
United States	West Virginia University	Morgantown	West Virginia
United States	Intermountain Medical Center	Murray	Utah
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Yale New Haven Hospital	New Haven	Connecticut
United States	Ochsner Health System	New Orleans	Louisiana
United States	Tulane University	New Orleans	Louisiana
United States	Columbia University Medical Center	New York	New York
United States	Mount Sinai Hospital New York	New York	New York
United States	Weill Cornell Medical College	New York	New York
United States	The Heart Group, PC	Newburgh	Indiana
United States	VA Palo Alto Health Care System	Palo Alto	California
United States	Cardiovascular Institute of Northwest Florida	Panama City	Florida
United States	Cardiac and Vascular Research Center of Northern Michigan/McLaren Northern Michigan	Petoskey	Michigan
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	Abrazo Arizona Heart Hospital	Phoenix	Arizona
United States	Banner University	Phoenix	Arizona
United States	Mayo Clinic Arizona	Phoenix	Arizona
United States	St. Joseph's Hospital and Medical Center/ Barrow Neurological Institute	Phoenix	Arizona
United States	UPMC Presbyterian University Hospital	Pittsburgh	Pennsylvania
United States	VA Pittsburgh Healthcare	Pittsburgh	Pennsylvania
United States	Maine Medical Center	Portland	Maine
United States	Oregon Health & Science University	Portland	Oregon
United States	Providence Brain and Spine Institute	Portland	Oregon
United States	The Miriam Hospital	Providence	Rhode Island
United States	North Carolina Heart & Vascular Research	Raleigh	North Carolina
United States	Mayo Clinic Rochester	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	Mercy Health Riverside	Rockford	Illinois
United States	St. Francis Hospital	Roslyn	New York
United States	William Beaumont Hospital	Royal Oak	Michigan
United States	St. Cloud Hospital	Saint Cloud	Minnesota
United States	John Cochran St. Louis Medical Center	Saint Louis	Missouri
United States	Mercy Hospital	Saint Louis	Missouri
United States	George E. Wahlen Department of Veterans Affairs Medical Center	Salt Lake City	Utah
United States	University of Utah Hospitals and Clinics	Salt Lake City	Utah
United States	Kaiser Permanente	San Diego	California
United States	Kaiser Permanente Northern California	San Francisco	California
United States	San Francisco VA Medical Center	San Francisco	California
United States	University of California San Francisco	San Francisco	California
United States	HonorHealth Scottsdale Osborn Medical Center	Scottsdale	Arizona
United States	Swedish Medical Center	Seattle	Washington
United States	University of Washington Medicine-Harborview Medical Center	Seattle	Washington
United States	VA Puget Sound Health Care System	Seattle	Washington
United States	North Central Heart Institute	Sioux Falls	South Dakota
United States	Providence Sacred Heart Medical Center	Spokane	Washington
United States	Cox Medical Center	Springfield	Missouri
United States	Mercy Medical Research Institute	Springfield	Missouri
United States	Prairie Heart/St. John's Hospital	Springfield	Illinois
United States	Stanford University Medical Center	Stanford	California
United States	St. Joseph's Medical Center	Stockton	California
United States	Crouse Hospital	Syracuse	New York
United States	White Oak Medical Center	Takoma Park	Maryland
United States	Tallahassee Neurological Clinic	Tallahassee	Florida
United States	Tampa General Hospital /University of South Florida	Tampa	Florida
United States	Jobst Vascular Institute/Toledo Hospital	Toledo	Ohio
United States	Mercy Health St.Vincent Medical Center	Toledo	Ohio
United States	Providence Little Company of Mary Medical Center	Torrance	California
United States	University of Arizona	Tucson	Arizona
United States	St. John Clinical Research Institute	Tulsa	Oklahoma
United States	Washington Hospital Center/Medstar	Washington	District of Columbia
United States	Coastal Carolina Surgical Associates PA	Wilmington	North Carolina
United States	Winchester Medical Center	Winchester	Virginia
United States	Novant Health/Forsyth Medical Center	Winston-Salem	North Carolina
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina
United States	University of Massachusetts Memorial Hospital	Worcester	Massachusetts
United States	Pinnacle Health Cardiovascular Institute	Wormleysburg	Pennsylvania
United States	Lankenau Medical Center	Wynnewood	Pennsylvania
United States	Berks Cardiologists / St. Joseph's Medical Center	Wyomissing	Pennsylvania
United States	Trinity Health/ Michigan Heart	Ypsilanti	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
Thomas G. Brott, M.D.	National Institute of Neurological Disorders and Stroke (NINDS)

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Israel,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Stroke and death	The primary outcome is the composite of stroke plus death within 44 days after randomization and ipsilateral stroke thereafter up to 4 years.	4 years
Secondary	Cognitive Function	The assess if MEDICAL management differs from CAS, and differs from CEA, to maintain the level of cognitive function at the 4-year assessment.	4 years
Secondary	Major Stroke	if there are treatment differences in the incidence of major stroke at 4-years among all arms of the study	4 years
Secondary	Effect modification	Potential effect modification of the CAS or CEA versus MEDICAL differences, based on patient age, sex, severity of carotid stenosis, restenosis, risk factor level, and duration of asymptomatic period.	4 years

External Links

•   CREST-2 Website
•   Mayo Clinic Clinical Trials