Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST)

OVERVIEW
The purpose of the CREST study is to compare the relatively new procedure of stent-assisted carotid angioplasty (CAS) to the traditional and accepted surgical approach of carotid endarterectomy (CEA) for the treatment of carotid artery stenosis to prevent recurrent strokes in those patients who have had a TIA (transient ischemic attack) or a mild stroke.

PURPOSE
Your brain is dependent on blood and oxygen supplied from your carotid arteries (the main blood vessels in your neck that supply blood and oxygen to your brain).  A narrowing of one of the carotid arteries in the neck, which supplies blood to the brain, can be the cause of brain damage or stroke. It is therefore important to remove this narrowing to prevent stroke.

Carotid endarterectomy is an operation on the carotid artery where the thickened narrow area of the artery is removed through an incision in the neck. Carotid artery stenting is a procedure in which a small tube made of wire mesh, called a stent, is placed inside the thickened/narrow artery in the neck. Once in position across the narrowing, the stent is opened out where it acts like a spring to keep the artery open.

The investigators are conducting a research trial to compare the results of treating blockages or narrowing in carotid arteries with carotid endarterectomy or carotid stenting.

Carotid endarterectomy combined with medication is often the standard treatment for patients with carotid narrowing.  This surgery has been shown to reduce the risk of stroke and death when compared to medications alone.  

The investigators will also look to find out more about the RX ACCULINK™ Carotid Stent System and the RX ACCUNET™ Embolic Protection System.  As part of the procedure to implant the carotid stent, your physician will use both of these systems. 

The RX ACCULINK™ Carotid Stent System is the wire mesh (stent) placed in the blood vessel during the stenting procedure. The RX ACCUNET™ System is used to capture blood clots that could break off from a blood vessel during carotid artery stenting procedure. 

WHY HAVE YOU BEEN ASKED TO TAKE PART IN THIS STUDY?
You are being asked to take part in this research study because you have been told that an artery in your neck that supplies blood to your brain is too narrow or thick. Some cholesterol plaques are lining the walls of your artery and causing a decrease in the normal blood flow to your brain. This increases your chances of having a stroke.

WHO SHOULD NOT BE IN THE RESEARCH STUDY?
You will be excluded from the study for any one of the following reasons:

• You are not at least 18 years of age
• You or your caregiver cannot or will not give informed consent
• You have a stroke that is presently continuing to cause damage to your brain.
• You have a history of intolerance or allergic reaction to any of the study medications, including blood thinning medications such as aspirin, ticlopidine, and/or clopidogrel
• You will refuse blood transfusions
• You have severe mental confusion
• You have any condition that precludes your involvement in the study, such as being severely over weight or having high blood pressure not controlled with medications
• You have had any severe neurological illnesses within the past two years
• You are actively participating in another drug or device trial that has not completed the required protocol follow-up period
• You have had a heart attack within the past 30 days
• You have had a recent bleeding ulcer.
• You do not agree to the required clinical follow-up evaluations
• You have an adverse reaction to anesthesia
• You have weakness from a previous stroke on the same side of your body
• You have an irregular heart beat called atrial fibrillation
• You have a high risk of complications associated with surgery because of your medical history/condition as determined by your doctor

Both males and females will be evaluated for this study.  Females must be of non-childbearing potential or have a negative pregnancy test confirmed, which will be obtained as the standard of care during the initial evaluation for the required procedure/surgery.

HOW LONG WILL YOU BE IN THE RESEARCH STUDY?
After you are discharged from the hospital, whether you have carotid surgery or carotid stenting, you will need to return to visit your doctor for follow-up examinations at one month, six months, twelve months after you were treated, and every six months thereafter until you are notified by your doctor that the study is completed. Your doctor may decide to take you off this research study at any time if he feels it is in your best medical interest.  You will not be required to participate at any time after the study is complete.

WHY IS THIS RESEARCH BEING DONE?
The purpose of this research is to compare the results of treating thickening/narrowing in carotid arteries with either carotid endarterectomy (surgery) or carotid stenting, using the ACCULINK™ Carotid Stent System and the use of ACCUNET™ Embolic Protection System during the carotid stenting procedure.    

WHO IS CONDUCTING THE RESEARCH STUDY?
This study is sponsored by the National Institute of Neurological Disorders and Stroke (NINDS), which is a part of the National Institutes of Health (NIH), and also the University of Medicine and Dentistry (UMDNJ). The study is directed by Andrew Ringer, M.D., the researcher at the University of Cincinnati Medical Center.

HOW MANY PEOPLE WILL TAKE PART IN THE RESEARCH STUDY?
Sixty or more different US sites will take part in the study.  A total of 4,300 subjects will take part in all across the country.  Each site including the University of Cincinnati Medical Center, will enroll approximately 40-45 patients during the randomization phase of this study. 

WHAT IS INVOLVED IN THE RESEARCH STUDY?
If you agree to participate in this study, by signing the informed consent form, your doctor will review the entire procedure with you.  The following is a general description of what will occur.

You will be randomized (assigned randomly like the flip of a coin) to receive carotid endarterectomy (surgery) or the carotid stenting procedure to treat the narrowing/ thickness blocking the normal flow of blood in your carotid artery. In this study, you have an equal chance of receiving either treatment.  Neither you nor doctor will know which of the two treatments will be done, until after you have consented to participate in the study.

If you are assigned to the surgical treatment to have a carotid endarterectomy, 48 hours before your scheduled surgery you will be required to take aspirin in preparation for your procedure.  This medication is intended to prevent your blood from clotting and will be prescribed by your doctor.  The day of your procedure, an intravenous (into your veins) line will be started to give you fluids and medicines for sedation and pain prevention.  Carotid endarterectomy consists of surgical removal of the plaque (artery blockage) and is performed under general anesthesia (while you are asleep) or local anesthesia (medication injected into your neck like that used by dentists).  Your doctor and anesthesiologist will decide which form of anesthesia is best for you.

During the endarterectomy, your surgeon will make an incision in your neck to expose your carotid artery.  The surgeon will then open up the artery and remove the plaque that is attached to the artery wall.  The artery and then the incision will be sewn closed. 

After endarterectomy surgery, your doctor will have you take aspirin daily for at least 1 year.  In addition to this, your doctor may ask you to take other medications, such as medicine to control blood pressure.

If you are assigned to the carotid stenting procedure, as early as 48 hours before your scheduled carotid stenting procedure, you will be required to take blood thinning medications called ticlopidine and/or clopidogrel, in preparation for your procedure. These medications are prescribed by your doctor and are intended to help prevent your blood from forming harmful clots in your body.

At the hospital, on the day of your scheduled procedure your skin will be numbed and a catheter will be placed in an artery in the groin.  Using x-ray visualization, the catheter will be advanced to the arteries supplying blood to the brain and x-ray dye will be injected to obtain pictures of these arteries.  Your doctor will use embolic protection (the attempt to prevent a clot to break off during the procedure), the RX ACCUNET™ System, unless he or she believes it may be unsafe due to your medical condition.  The system will be advanced through the catheter, positioned beyond the narrowed section of the carotid artery, and expanded so that it may capture embolic material.  Your carotid artery may then be enlarged with a balloon catheter if necessary.  The stent will then be placed in the narrowed section.

The carotid stent is an elastic-like metallic supporting frame that has been placed onto a catheter and covered with a retractable sheath, to hold it in place while it is being positioned in the carotid artery.  When the stent is positioned across the narrowed segment of the carotid artery, it is released by pulling back on the sheath, and it is allowed to expand on its own.  When released, the stent presses against the artery wall to enlarge the blood vessel at the point of narrowing and may prevent fatty deposits on the artery wall from breaking off and possibly causing a stroke.  The catheter is then removed and another balloon catheter may be used to further expand the narrowed portion of the artery.  If used, the RX ACCUNET™ System will then be closed and removed, leaving only the stent in place.  Over a period of three to four weeks, the inner lining of the artery will grow over the stent surface, and the stent will become a permanent part of your artery.

After the procedure, you will be required to take additional blood thinning medications called clopidogrel or ticlopidine, daily for a period of four weeks and aspirin daily for at least one year.  For the first two to fours weeks, the combination of the aspirin and the medication keeps formation of blood clots to a minimum.  This is in addition to any medications your doctor my ask you to take, such as medicine to control blood pressure.

After you are discharged from the hospital, whether you have carotid surgery or carotid stenting, you will need to return to visit your doctor for follow-up examinations at one month, six months, twelve months after your were treated, and every six months thereafter until you are notified by your doctor that the study is completed.

At the time of these visits, you will be asked about any symptoms you may have experienced.  If you are taking ticlopidine, you will have blood tests (approximately 1 teaspoon of blood) at two weeks and one month.  You will have additional blood tests (approximately 1 teaspoon of blood) at six months, 12 months and then every year until the study is complete.  You will also have a carotid duplex ultrasound performed at some of these visits.  For this test, a probe is placed against the outside of your neck, over the carotid artery.  Sound waves from the probe are bounced off the artery to produce an image of the blood flowing through the artery. 

You will receive phone calls from the study nurse at three months and nine months after you were treated, and every six months thereafter until your doctor notifies you that the study is completed.  Additionally, a designated study staff member will contact you by phone at two weeks after your study treatment.  During this call you will be asked a set of standard questions regarding your well-being and state of health known as a Quality of Life questionnaire.  Other tests may be ordered by your doctor as a routine part of your care.

This study contains a health economics review that will be done to assess for reasonable medical expenses, which occur as a direct result of your participation in this clinical trial.  Representatives of the Economic and Quality of Life Assessment Group of the Harvard Clinical Research Institute (HCRI) may obtain copies of the signature page of this informed consent in order to collect hospital bills from the Patient Accounting Department at any hospital to which you are admitted from the time of enrollment in CREST through the study follow-up period.

SUMMARY OF REQUIRED FOLLOW-UP VISITS AND PROCEDURES

WHAT ARE THE RISKS AND DISCOMFORTS OF THE RESEARCH STUDY?
When carotid endarterectomy is performed by a highly experienced surgeon on patients who are at low risk for surgical complications, the risk of minor stroke (symptoms go away in 30 days) or major stroke is less than 5% and chance of death is between 1-2%.  There may be discomfort at the site of the surgical incision.  Surgery may cause damage to the blood vessels resulting in bleeding or vessel narrowing.  Depending on the severity and area of brain involved, either of these complications could result in worsening neurologic function or death.

There may be discomfort at the site of the surgical incision.  Wound complications including moderate bleeding and infection may occur in a small number of cases (less than 5%). 

Additional risks associated with carotid endarterectomy or anesthesia include, temporary or permanent damage to nerves in your face, lung infection, heart attack, kidney failure, low blood pressure, abnormal heart rhythms, and death.

Potential risks associated with the stent procedure (which uses the ACCUNET™ System and may include the embolic protection system) include:

• minor stroke (symptoms go away within 30 days), major stroke, kidney failure, bleeding, infection, or death
• allergic reaction to the contrast material used (x-ray dye) and/or medications used
• blockage to the artery in the leg that may require surgical repair
• need for a blood transfusion
• low blood pressure
• abnormal heart rhythms
• discomfort or bleeding at the insertion site of the catheter
• damage to the blood vessels such as bleeding or vessel narrowing caused by the enlarging of the carotid artery
• worsening neurological function, depending on the severity and area of the brain involved
• rare possibility that the stent may move following placement
• need to place another stent if the stent is released before reaching the narrowed section of the vessel, which may slightly increase the risk of blood clot formation
• re-narrowing of  treated area, which may require additional treatment, such as repeat angioplasty and/or surgery to reduce the chance of stroke that can be caused by re-narrowing
• there may be additional risk to you, the nature of which are unknown

The metals used to make the stents have been implanted for many years in human tissues, but there is no long-term information about the potential side effects of use of such metals in the carotid artery.

Potential risks although rare, that may be associated with the RX ACCUNET™ System include:

• clotting off of the filter used in this system
• filter entanglement on the stent or other damage to the stent
• failure to recover the filter could result in the filter coming off and remaining inside your vessel.  In such case, your physician would use additional treatments to remove the filter or stabilize it in the vessel so that it does not obstruct blood flow.  This could include surgery of the carotid artery, or placement of another stent, or other maneuvers as determined by your doctor.
• mechanical failure of the device

Potential risks that may be associated with the medication include:

• side effects from the use of aspirin, which may include bleeding, , stomach ulcers (bleeding or non-bleeding), or other bleeding problems – if bleeding occurs or if it is necessary to perform surgery, a blood transfusion may become necessary
• side effects from the use of clopidogrel, a mild blood thinner, may include bleeding problems, abdominal pain, stomach ulcers, and nausea
• side effects from the use of ticlopidine (if used instead of clopidogrel) may include bleeding problems, increased cholesterol and diarrhea.  In rare instances found in 1-2% of people, this medication may decrease your body’s ability to fight off infection, which could result in serious infection and, very rarely, death.  Blood samples will be taken at two and four weeks to monitor for this and some discomfort may result from these blood draws.

Even with a successful procedure, stenting or surgery, there is a chance that the treated area could become narrow again.  This may require additional treatment, such as repeat angiogram and/or surgery to reduce the chance of stroke that can be caused by the re-narrowing.

This treatment may involve additional risks to you, the nature of which are unknown.  In addition, this procedure may involve unforeseeable risks to you or your fetus if you are pregnant.  Therefore, pregnant women are excluded from this study.  Should you become pregnant while taking part in this study, you must immediately notify your doctor.

These are the known risks of your involvement in the study.  However, there may be unforeseen risks not mentioned above.

ARE THERE ANY REPRODUCTIVE RISKS?
Because the risks of this procedure to a fetus are unknown, pregnant women or breastfeeding mothers will not be included in this study.  If you are of childbearing potential, adequate birth control measures, (as explained by your physician), must be followed during the stenting or surgical treatment period to participate in this study.  You agree to notify your study doctor immediately if you become pregnant at any time during your participation in this study. A pregnancy test will be performed for all women of childbearing potential prior to the treatment period of the study. 

ARE THERE BENEFITS TO TAKING PART IN THE RESEARCH STUDY?
If you agree to take part in this research study, there is no guaranteed benefit.  The purpose of this research study is to determine the relative risks and benefits of a specific medical treatment and/or device. While previous studies have suggested that carotid endarterectomy may not be as beneficial to women as to men, this study will allow us to look at possible differences between men and women.

WHAT OTHER CHOICES FOR CARE ARE THERE?
Participation in this research is entirely voluntary.  You may refuse to participate or withdraw at any time without jeopardizing the medical care you will receive at this institution.  Alternative therapy includes medical treatment with drugs (e.g., aspirin) that help slow down the clotting process of your blood and help reduce the risk of stroke.  If you do not wish to participate in this study, you may choose to undergo surgical or other medical treatment if appropriate.  You may also undergo the surgical treat or carotid endarterectomy without taking part in this study. Your doctor can discuss any alternatives as they apply to your individual situation.

HOW WILL INFORMATION ABOUT YOU BE KEPT PRIVATE AND CONFIDENTIAL?
Every effort will be made to maintain the confidentiality of your study records. Agents of the United States Food and Drug Administration, other applicable government regulatory agencies, National Institutes of Neurological Disorders and Stroke (NINDS), Harvard Clinical Research Institute (HCRI) and Guidant Corporation, or its representatives, and the University of Cincinnati will be allowed to inspect sections of your medical and research records related to this study. The data from the study may be published; however, you will not be identified by name. Your identity will remain confidential unless disclosure is required by law. The investigators continue to have ethical and legal obligations to report abuse or neglect and to prevent you from carrying out any threats to do serious harm to yourself or others. If keeping information private would immediately put you or someone else in danger, the investigators would release information to protect you or another person.

WHAT ARE YOUR COSTS TO BE IN THIS STUDY?
All medical care costs will be the responsibility of you and your insurance company and will not be assumed by the University of Cincinnati, the University Hospital, the NIH/NINDS, UMDNJ or Guidant Corp.  The routine cost for the stent procedure or surgery will be billed to your insurance carrier or national health service such as Medicare, as applicable.

WILL YOU BE PAID TO PARTICIPATE IN THIS RESEARCH STUDY?
No compensation will be paid to you for participation in this trial.

WHAT COMPENSATION IS AVAILABLE IN CASE OF INJURY?
In the event that you become ill or injured from participating in this research study, emergency medical care will be provided to you.  The University of Cincinnati will decide on a case by case basis whether to reimburse you for your out of pocket health care expenses.  No other compensation is available.

WHAT ARE YOUR RIGHTS AS A PARTICIPANT?
You may choose either to take part or not to take part in this research study. If you decide to take part, you may decide to leave the study at any time. Leaving the study will not result in any penalty or loss of benefits to you. The investigators will tell you about new information that may affect your health, welfare, or willingness to stay in this study.

If you have questions about the study, you will have a chance to talk to one of the study staff or your regular doctor. Do not sign this form unless you have had the chance to ask questions and have received satisfactory answers.

Nothing in this consent form waives any legal rights you may have nor does it release the investigator, the sponsor, the institution, or its agents from liability for negligence.

WHO DO YOU CALL IF YOU HAVE QUESTIONS OR PROBLEMS?
If you have questions about this research study or to report a research-related injury, you can contact the researcher, Dr. Andrew Ringer at 513-475-8662.  If you have general questions about giving consent or your rights as a research participant in this research study, you can call the University of Cincinnati Medical Institutional Review Board at 513-558-5259.

Study design
This is a Phase III randomized, multicenter treatment study.

Location & contact
Andrew Ringer, MD (Principal investigator)
University of Cincinnati Medical Center
222 Piedmont Avenue, #3100
Cincinnati, OH 45219
Telephone: 513-558-5398
Fax: 513-558-7702
Email: suzanne.kempisty-cliver@uc.edu

More information
More info is available for this study.
CREST website
Start date: 6/2004
Close date: upon enrollment of 60-65 patients.
Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)
Study ID number: #99-705, UC IRB Study #04-3-5-2

Understanding clinical trials