CREST-2: Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial

Sponsor

Thomas G. Brott, M.D. (Other)

Overall Status

Recruiting

CT.gov ID

NCT02089217

Collaborator

National Institute of Neurological Disorders and Stroke (NINDS) (NIH)

2,480

Enrollment

159

Locations

Arms

134

Duration (Months)

15.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Carotid Stenosis	Procedure: Carotid endarterectomy (CEA) Device: Carotid Stenting (CAS) Other: Intensive Medical Management - no CEA Other: Intensive Medical Management - no CAS	N/A

Detailed 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

2480 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

CREST-2 is two parallel multi-center randomized, observer-blinded endpoint clinical trials.CREST-2 is two parallel multi-center randomized, observer-blinded endpoint clinical trials.

Masking:

Single (Investigator)

Masking Description:

CREST-2 is two parallel multi-center randomized, observer-blinded endpoint clinical trials.

Primary Purpose:

Prevention

Official Title:

Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial

Study Start Date :

Dec 1, 2014

Anticipated Primary Completion Date :

Feb 1, 2026

Anticipated Study Completion Date :

Feb 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Carotid Endarterectomy (CEA) Carotid Endarterectomy	Procedure: Carotid endarterectomy (CEA) Carotid endarterectomy
Active Comparator: Carotid Stenting (CAS) Carotid Stenting	Device: Carotid Stenting (CAS) Carotid stenting
Experimental: Intensive Medical Management - no CEA Intensive Medical Management alone - no CEA	Other: Intensive Medical Management - no CEA Intensive Medical Management alone - no CEA
Experimental: Intensive Medical Management - no CAS Intensive Medical Management alone - no CAS	Other: Intensive Medical Management - no CAS Intensive Medical Management alone - no CAS

Outcome Measures

Primary Outcome Measures

Stroke and death [4 years]
The primary outcome is the composite of stroke plus death within 44 days after randomization and ipsilateral stroke thereafter up to 4 years.

Secondary Outcome Measures

Cognitive Function [4 years]
The assess if MEDICAL management differs from CAS, and differs from CEA, to maintain the level of cognitive function at the 4-year assessment.
Major Stroke [4 years]
if there are treatment differences in the incidence of major stroke at 4-years among all arms of the study
Effect modification [4 years]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

35 Years to 100 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

General Inclusion Criteria

Patients ≥35 years old.
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:

an end diastolic velocity ≥100 cm/s, or
internal carotid/common carotid artery peak systolic velocity ratio ≥4.0, or
CTA with ≥ 70% stenosis, or
MRA with ≥ 70% stenosis.
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
Patients must have a modified Rankin Scale score of 0 or 1 at the time of informed consent.
Women must not be of childbearing potential or, if of childbearing potential, have a negative pregnancy test prior to randomization.
Patients must agree to comply with all protocol-specified follow-up appointments.
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.
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).
Carotid stenosis must be treatable with CEA, CAS, or either procedure.

General Exclusion Criteria

Intolerance or allergic reaction to a study medication without a suitable management alternative.
GI hemorrhage within 1 month prior to enrollment that would preclude antiplatelet therapy.
Prior major ipsilateral stroke in the past with substantial residual disability (mRS ≥

that is likely to confound study outcomes.

Severe dementia.
History of major symptomatic intracranial hemorrhage within 12 months that was not related to anticoagulation.
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.
Current neurologic illness characterized by fleeting or fixed neurologic deficits that cannot be distinguished from TIA or stroke.
Patient objects to future blood transfusions.
Platelet count <100,000/microliter or history of heparin-induced thrombocytopenia.
Anticoagulation with Phenprocoumon (Marcumar®), warfarin, or a direct thrombin inhibitor, or anti-Xa agents.
Chronic atrial fibrillation.
Any episode of atrial fibrillation within the past 6 months or history of paroxysmal atrial fibrillation that is deemed to require chronic anticoagulation.
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.
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).
Left Ventricular Ejection fraction <30% or admission for heart failure in prior 6 months.
Respiratory insufficiency with life expectancy < 4 years or FEV1 <30% of predicted value.
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.
Any major surgery, major trauma, revascularization procedure, or acute coronary syndrome within the past 1 month.
Either the serum creatinine is ≥ 2.5 mg/dl or the estimated GFR is < 30 cc/min.
Major (non-carotid) surgery/procedures planned within 3 months after enrollment.
Currently listed or being evaluated for major organ transplantation (i.e. heart, lung, liver, kidney).
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.
Inability to understand and cooperate with study procedures or provide informed consent.
Non-atherosclerotic carotid stenosis (dissection, fibromuscular dysplasia, or stenosis following radiation therapy).
Previous ipsilateral CEA or CAS.
Ipsilateral internal or common carotid artery occlusion.
Intra-carotid floating thrombus.
Ipsilateral intracranial aneurysm > 5 mm.
Extreme morbid obesity that would compromise patient safety during the procedure or would compromise patient safety during the periprocedural period.
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:

Serious adverse reaction to anesthesia not able to be overcome by pre-medication.
Distal/intracranial stenosis greater than index lesion.
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:

Allergy to intravascular contrast dye not amenable to pre-medication.
Type III, aortic arch anatomy.
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.
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.
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).)

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.
Inability to deploy or utilize an FDA-approved Embolic Protection Device (EPD).
Non-contiguous lesions and long lesions (>3 cm).
Qualitative characteristics of stenosis and stenosis-length of the carotid bifurcation (common carotid) and/or ipsilateral external carotid artery, that preclude safe sheath placement.
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.
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The University of Alabama at Birmingham	Birmingham	Alabama	United States	35233
2	Brookwood Medical Center	Birmingham	Alabama	United States	35243
3	Huntsville Hospital/ Heart Center Research Alabama	Huntsville	Alabama	United States	35801
4	Banner University	Phoenix	Arizona	United States	85006
5	St. Joseph's Hospital and Medical Center/ Barrow Neurological Institute	Phoenix	Arizona	United States	85013
6	Abrazo Arizona Heart Hospital	Phoenix	Arizona	United States	85016
7	Mayo Clinic Arizona	Phoenix	Arizona	United States	85054
8	HonorHealth Scottsdale Osborn Medical Center	Scottsdale	Arizona	United States	85251
9	University of Arizona	Tucson	Arizona	United States	85724
10	Central Arkansas Veteran's Healthcare System	Little Rock	Arkansas	United States	72143
11	Mission Cardiovascular Research	Fremont	California	United States	94538
12	Kaiser Permanente Los Angeles	Los Angeles	California	United States	90027
13	Keck Medical Center of University of Southern California	Los Angeles	California	United States	90033
14	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
15	University of California Los Angeles (UCLA)	Los Angeles	California	United States	90095
16	VA Palo Alto Health Care System	Palo Alto	California	United States	94304
17	Kaiser Permanente	San Diego	California	United States	92116
18	Kaiser Permanente Northern California	San Francisco	California	United States	94115
19	San Francisco VA Medical Center	San Francisco	California	United States	94121
20	University of California San Francisco	San Francisco	California	United States	94143
21	Stanford University Medical Center	Stanford	California	United States	94305
22	St. Joseph's Medical Center	Stockton	California	United States	95204
23	Providence Little Company of Mary Medical Center	Torrance	California	United States	90503
24	St. Mary's Medical Center	Grand Junction	Colorado	United States	81501
25	Medical Center of the Rockies	Loveland	Colorado	United States	80538
26	Hartford Hospital	Hartford	Connecticut	United States	06102
27	Yale New Haven Hospital	New Haven	Connecticut	United States	06520
28	Washington Hospital Center/Medstar	Washington	District of Columbia	United States	20010
29	Morton Plant Hospital	Clearwater	Florida	United States	33756
30	University of Florida Health at Shands	Gainesville	Florida	United States	32610
31	Lyerly Neurosurgery	Jacksonville	Florida	United States	32207
32	UF Jacksonville	Jacksonville	Florida	United States	32209
33	First Coast Cardiovascular Institute	Jacksonville	Florida	United States	32216
34	Mayo Clinic	Jacksonville	Florida	United States	32224
35	Mount Sinai Medical Center of Florida	Miami Beach	Florida	United States	33140
36	University of Miami Hospital	Miami	Florida	United States	33136
37	Miami Cardiac and Vascular Institute at Baptist Hospital of Miami	Miami	Florida	United States	33176
38	Cardiovascular Institute of Northwest Florida	Panama City	Florida	United States	32401
39	Tallahassee Neurological Clinic	Tallahassee	Florida	United States	32308
40	Tampa General Hospital /University of South Florida	Tampa	Florida	United States	33606
41	Atlanta VA Medical Center	Atlanta	Georgia	United States	30033
42	Emory University	Atlanta	Georgia	United States	30322
43	Southern Illinois Healthcare	Carbondale	Illinois	United States	62901
44	The University of Chicago Medical Center	Chicago	Illinois	United States	60637
45	Northwestern University	Evanston	Illinois	United States	60208
46	Loyola University Medical Center	Maywood	Illinois	United States	60135
47	Mercy Health Riverside	Rockford	Illinois	United States	61114
48	Prairie Heart/St. John's Hospital	Springfield	Illinois	United States	62701
49	Franciscan St. Francis Health	Indianapolis	Indiana	United States	46237
50	The Heart Group, PC	Newburgh	Indiana	United States	47630
51	University of Iowa	Iowa City	Iowa	United States	52242
52	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
53	Baptist Health Lexington	Lexington	Kentucky	United States	40503
54	University of Kentucky Hospital	Lexington	Kentucky	United States	40536
55	University of Louisville	Louisville	Kentucky	United States	40202
56	Tulane University	New Orleans	Louisiana	United States	70112
57	Ochsner Health System	New Orleans	Louisiana	United States	70121
58	Maine Medical Center	Portland	Maine	United States	04102
59	University of Maryland VA	Baltimore	Maryland	United States	21201
60	John Hopkins Medical Institution	Baltimore	Maryland	United States	21224
61	White Oak Medical Center	Takoma Park	Maryland	United States	20912
62	St. Elizabeth's Medical Center	Boston	Massachusetts	United States	02135
63	Massachusetts General Hospital	Boston	Massachusetts	United States	02144
64	Beth Israel Deaconess Medical Center (BIDMC)	Boston	Massachusetts	United States	02215
65	University of Massachusetts Memorial Hospital	Worcester	Massachusetts	United States	01605
66	VA Ann Arbor Healthcare System	Ann Arbor	Michigan	United States	48105
67	University of Michigan Hospital and Health Systems	Ann Arbor	Michigan	United States	48109
68	Henry Ford Health System	Detroit	Michigan	United States	48202
69	Michigan Vascular Center/McLaren- Flint	Flint	Michigan	United States	48532
70	Sparrow Clinical Research Institute	Lansing	Michigan	United States	48912
71	Cardiac and Vascular Research Center of Northern Michigan/McLaren Northern Michigan	Petoskey	Michigan	United States	49770
72	William Beaumont Hospital	Royal Oak	Michigan	United States	48073
73	Trinity Health/ Michigan Heart	Ypsilanti	Michigan	United States	48197
74	Minneapolis Clinic of Neurology, Ltd./ North Memorial Medical Center	Golden Valley	Minnesota	United States	55422
75	Hennepin County Medical Center	Minneapolis	Minnesota	United States	55415
76	University of Minnesota	Minneapolis	Minnesota	United States	55455
77	Mayo Clinic Rochester	Rochester	Minnesota	United States	55905
78	St. Cloud Hospital	Saint Cloud	Minnesota	United States	56303
79	John Cochran St. Louis Medical Center	Saint Louis	Missouri	United States	63106
80	Mercy Hospital	Saint Louis	Missouri	United States	63141
81	Cox Medical Center	Springfield	Missouri	United States	65807
82	Mercy Medical Research Institute	Springfield	Missouri	United States	65807
83	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
84	Cooper University	Camden	New Jersey	United States	08103
85	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
86	SUNY Buffalo	Buffalo	New York	United States	14203
87	The Feinstein Institute of Medical Research	Manhasset	New York	United States	11030
88	Mount Sinai Hospital New York	New York	New York	United States	10029
89	Columbia University Medical Center	New York	New York	United States	10032
90	Weill Cornell Medical College	New York	New York	United States	10065
91	University of Rochester	Rochester	New York	United States	14642
92	St. Francis Hospital	Roslyn	New York	United States	11576
93	Crouse Hospital	Syracuse	New York	United States	13210
94	Duke University Medical Center	Durham	North Carolina	United States	27710
95	North Carolina Heart & Vascular Research	Raleigh	North Carolina	United States	27607
96	Coastal Carolina Surgical Associates PA	Wilmington	North Carolina	United States	28401
97	Novant Health/Forsyth Medical Center	Winston-Salem	North Carolina	United States	27103
98	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
99	University of Cincinnati Medical Center	Cincinnati	Ohio	United States	45219
100	Louis Stokes Cleveland VA Medical Center	Cleveland	Ohio	United States	44106
101	University Hospitals Cleveland Medical Center	Cleveland	Ohio	United States	44106
102	Ohio State Medical Center	Columbia	Ohio	United States	43210
103	OhioHealth Research Institute	Columbus	Ohio	United States	43214
104	Jobst Vascular Institute/Toledo Hospital	Toledo	Ohio	United States	43606
105	Mercy Health St.Vincent Medical Center	Toledo	Ohio	United States	43608
106	St. John Clinical Research Institute	Tulsa	Oklahoma	United States	74104
107	Providence Brain and Spine Institute	Portland	Oregon	United States	97225
108	Oregon Health & Science University	Portland	Oregon	United States	97239
109	Lehigh Valley Hospital - Network Office of Research	Allentown	Pennsylvania	United States	18103
110	UPMC Altoona	Altoona	Pennsylvania	United States	16601
111	Doylestown Hospital	Doylestown	Pennsylvania	United States	18901
112	UPMC Hamot	Erie	Pennsylvania	United States	16550
113	PennState Health Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17018
114	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
115	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania	United States	19107
116	UPMC Presbyterian University Hospital	Pittsburgh	Pennsylvania	United States	15213
117	VA Pittsburgh Healthcare	Pittsburgh	Pennsylvania	United States	15240
118	Pinnacle Health Cardiovascular Institute	Wormleysburg	Pennsylvania	United States	17043
119	Lankenau Medical Center	Wynnewood	Pennsylvania	United States	19096
120	Berks Cardiologists / St. Joseph's Medical Center	Wyomissing	Pennsylvania	United States	19610
121	The Miriam Hospital	Providence	Rhode Island	United States	02906
122	Medical University of South Carolina	Charleston	South Carolina	United States	29425
123	North Central Heart Institute	Sioux Falls	South Dakota	United States	57108
124	CVA Heart Institute	Kingsport	Tennessee	United States	37660
125	Tennova Healthcare/ Turkey Creek Medical Center	Knoxville	Tennessee	United States	37934
126	Baptist Memorial Hospital	Memphis	Tennessee	United States	38017
127	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
128	Seton Medical Center Austin	Austin	Texas	United States	78705
129	Cardiothoracic and Vascular Surgeons	Austin	Texas	United States	78756
130	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75235
131	Valley Baptist Medical Center	Harlingen	Texas	United States	78551
132	Houston Methodist Hospital	Houston	Texas	United States	77030
133	Memorial Hermann Texas Medical Center	Houston	Texas	United States	77030
134	Intermountain Medical Center	Murray	Utah	United States	84107
135	University of Utah Hospitals and Clinics	Salt Lake City	Utah	United States	84132
136	George E. Wahlen Department of Veterans Affairs Medical Center	Salt Lake City	Utah	United States	84148
137	University of Virginia Health System	Charlottesville	Virginia	United States	22908
138	Inova Fairfax Health Care	Falls Church	Virginia	United States	22042
139	Winchester Medical Center	Winchester	Virginia	United States	22601
140	Overlake Hospital Medical Center	Bellevue	Washington	United States	98004
141	University of Washington Medicine-Harborview Medical Center	Seattle	Washington	United States	98104
142	VA Puget Sound Health Care System	Seattle	Washington	United States	98108
143	Swedish Medical Center	Seattle	Washington	United States	98122
144	Providence Sacred Heart Medical Center	Spokane	Washington	United States	99204
145	West Virginia University	Morgantown	West Virginia	United States	26554
146	Gundersen Clinic, Ltd	La Crosse	Wisconsin	United States	54601
147	University of Wisconsin	Madison	Wisconsin	United States	53792
148	Fiona Stanley Hospital	Perth		Australia
149	Vancouver General Hospital	Vancouver	British Columbia	Canada	V5Z 1M9
150	Nova Scotia Health Authority	Halifax	Nova Scotia	Canada	B3H 3A7
151	St. Michael's Hospital	Toronto	Ontario	Canada	M5B 1W8
152	St. Boniface Hospital	Winnipeg	Ontario	Canada	R2H 2A6
153	CHU de Québec/ Hôpital de l'Enfant-Jésus	Québec City	Quebec	Canada	G1J1Z4
154	Soroka University Medical Center	Be'er Sheva		Israel
155	Soroka University Vascular Surgery	Be'er Sheva		Israel
156	Rambam Healthcare	Haifa		Israel	3109601
157	Shaare-Zedek Medical Center	Jerusalem		Israel
158	Rabin Medical Center	Petach Tikva		Israel
159	Hospital Clinic Barcelona	Barcelona		Spain

Sponsors and Collaborators

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

Investigators

Principal Investigator: Thomas G. Brott, MD, Mayo Clinic
Principal Investigator: James F. Meschia, MD, Mayo Clinic
Principal Investigator: Brajesh K. Lal, MD, University of Maryland
Principal Investigator: George Howard, DrPH, University of Alabama at Birmingham