Cerebral Infarction, Ischemic Attack, Transient, Stroke
Conditions
Keywords
stroke, transient ischemic attack (TIA), carotid arteries, cerebral infarction
Brief summary
The purpose of this study is to determine if extracranial-intracranial bypass surgery when added to best medical therapy can reduce the subsequent risk of ipsilateral stroke in high-risk patients with recently symptomatic carotid occlusion and increased cerebral oxygen extraction fraction measured by positron emission tomography (PET).
Detailed description
The overall purpose of this research is to determine if a surgical operation called Extracranial-Intracranial Bypass can reduce the chance of a subsequent stroke in someone who has complete blockage in one main artery in the neck (the carotid artery) that supplies blood to the brain and has already suffered a small stroke. This surgery involves taking an artery from the scalp outside the skull, making a small hole in the skull and then connecting the scalp artery to a brain artery inside the skull. In this way the blockage of the carotid artery in the neck is bypassed and more blood can flow to the brain. In some people natural bypass arteries develop and the brain is already getting plenty of blood. These people have a low risk of stroke if they take medicine. In other people, no natural bypass arteries develop so less blood flows to their brains. This second group has a much higher risk of stroke while taking medicine, as high as 25-50% within the next two years. It is this second group of people who may benefit from having the bypass operation and who are the candidates for this study. This bypass surgery is considered experimental because it is not generally performed for this condition and it is unknown whether it leads to a decrease, an increase or no change in the risk of stroke. In order to determine if people fit into this second group of people who may benefit from the bypass operation they need to have a test called a PET scan. The PET scan measures the amount of blood that is getting to the brain and the amount of oxygen that the brain is using. The PET scan uses radioactive oxygen and water and is experimental (not approved by the United States Food and Drug Administration). If the PET scan shows that less blood is getting to the brain, there will be a 50-50 chance (like a coin toss) of receiving the bypass surgery or not. There will then be follow-up visits to the clinic one month later and then every three months for two years to check on the appropriate medical treatment that everyone will receive and to determine who has had a stroke. The study hypothesis is that extracranial-intracranial bypass surgery when added to best medical therapy can reduce by 40 percent subsequent stroke within two years in participants with recent TIA ('ministroke) or stroke (\</= 120 days) due to blockage of the carotid artery and reduced blood flow to the brain measured by PET.
Interventions
Surgical anastomosis of a superficial temporal artery branch to a middle cerebral artery branch through a small craniectomy plus best current practice medical therapy
best current practice medical therapy
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Washington University School of Medicine
University of Iowa
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Vascular imaging demonstrating occlusion of one or both internal carotid arteries. * Transient ischemic attack (TIA) or ischemic stroke in the hemispheric carotid territory of one occluded carotid artery. * Most recent qualifying TIA or stroke occurring within 120 days prior to projected performance date of PET. * Modified Barthel Index \> 12/20 (60/100). * Language comprehension intact, motor aphasia mild or absent. * Age 18-85 inclusive. * Competent to give informed consent. * Legally an adult. * Geographically accessible and reliable for follow-up.
Exclusion criteria
* Non-atherosclerotic carotid vascular disease. Blood dyscrasias: Polycythemia vera ,essential thrombocytosis, sickle cell disease (SS or SC). * Known heart disease likely to cause cerebral ischemia (echocardiography not required). This includes the following conditions ONLY: Prosthetic valve, Infective endocarditis, Left atrial or ventricular thrombus, Sick sinus syndrome, Myxoma, Cardiomyopathy with ejection fraction \<25%. This is an all-inclusive list. The following conditions are NOT EXCLUSIONS: Atrial fibrillation, patent foramen ovale, atrial septal aneurysm. * Other non-atherosclerotic condition likely to cause focal cerebral ischemia. * Any condition likely to lead to death within 2 years. * Other neurological disease that would confound follow-up assessment. * Pregnancy. * Subsequent cerebrovascular surgery planned which might alter cerebral hemodynamics. * Any condition which in the participating surgeon's judgment makes the subject an unsuitable surgical candidate. * Participation in any other experimental treatment trial. * Participation within the previous 12 months in any experimental study that included exposure to ionizing radiation. * Acute, progressing or unstable neurological deficit. Neurological deficit must be stable for 72 hours prior to the performance of PET. * If supplemental arteriography is required, allergy to iodine or x-ray contrast media, serum creatinine \> 3.0 mg/dl or other contraindication to arteriography. * If aspirin is to be used as antithrombotic therapy in the perioperative period, those with allergy or contraindication to aspirin are ineligible. * Medical indication for treatment with anticoagulant drugs, ticlopidine, clopidogrel or other antithrombotic medications such that these medications cannot be replaced with aspirin in the perioperative period as deemed necessary by the COSS neurosurgeon if the participant is randomized to surgical treatment. * Remediable medical conditions. Patients with the following conditions can become eligible if the exclusion criterion no longer applies within 120 days of onset of the most recent qualifying event: Uncontrolled diabetes mellitus (FBS \> 300 mg%/16.7 mmol/L), Uncontrolled hypertension (systolic BP\>180, diastolic BP \>110), Unstable angina, Uncontrolled hypotension (diastolic BP \< 65).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Surgical Group:Ipsilateral Ischemic Stroke in 2 Yrs From Randomization and All Stroke & Death Through 30d Post-surgery; Non-surgical Group:Ipsilateral Ischemic Stroke in 2 Yrs From Randomization and All Stroke & Death Through 30d Post-randomization | within 2 yrs of randomization | 2 yr Kaplan-Meier estimates of the proportions.Proportions expressed as percentages for reporting purposes. Ipsilateral ischemic stroke is defined as the clinical diagnosis of a focal neurological deficit due to cerebral ischemia clinically localizable within the internal carotid artery territory distally to the symptomatic occluded internal carotid artery that lasts for more than 24 hours. All stroke is defined as the clinical diagnosis of a focal deficit due to ischemia or hemorrhage clinically localizable to the brain that lasts for more than 24 hours. Death is of any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All Stroke | within 2 yrs of randomization | 2 yr Kaplan-Meier estimates of the proportions. All stroke is defined as the clinical diagnosis of a focal deficit due to ischemia or hemorrhage clinically localizable to the brain that lasts for more than 24 hours |
| Disabling Stroke | within two years after randomization | 2 yr Kaplan-Meier estimates of the proportions. Disabling stroke is defined as a modified Barthel Index of \<12/20 at the first scheduled return visit more than 3 months after the stroke occurred |
| Fatal Stroke | within 2 years after randomization | 2 yr Kaplan-Meier estimates of the proportions. Fatal stroke is a stroke that in the investigator's opinion led directly to the participants death within 30 days of occurrence |
| Death | within 2 years after randomization | 2 yr Kaplan-Meier estimates of the proportions. Death of any cause |
| Modified Rankin 0-2 | at 2 years after randomization or end of trial. Worst case imputed for death and missing values | Proportion with Modified Rankin score at 2 yrs, dichotomized 0-2 vs 3-6. The modifed Rankin (0-6) describes the degree of functional disability. A lower score indicates less functional disability. |
| Modified Barthel Index 19-20 | at 2 years after randomization or end of trial. Worst case imputed for death and missing values | Modified Barthel Index dichotomized 19-20 vs \<= 18. The modifed Barthel Index(0-20) describes the degree of independence in day-to-day self-care activities. A higher score indicates greater independence. |
| Summary SS-QOL Score | at 2 years after randomization or end of trial. Worst case imputed for death and missing values | Summary Stroke Specific Quality of Life score (1-4) askes how self-reported overall quality of life compares with with that before stroke. A higher score indicates is better. |
| Ipsilateral Ischemic Stroke in 2 Yrs From Randomization and All Stroke & Death Through 30d Post-surgery; Non-surgical Group:Ipsilateral Ischemic Stroke in 2 Yrs From Randomization and All Stroke & Death Through 30d Post-randomization | within 2 years of randomization | 2 yr Kaplan-Meier estimates of the proportions.Proportions expressed as percentages for reporting purposes. Ipsilateral ischemic stroke is defined as the clinical diagnosis of a focal neurological deficit due to cerebral ischemia clinically localizable within the internal carotid artery territory distally to the symptomatic occluded internal carotid artery that lasts for more than 24 hours. All stroke is defined as the clinical diagnosis of a focal deficit due to ischemia or hemorrhage clinically localizable to the brain that lasts for more than 24 hours. Death is of any cause. |
| Modified Rankin 0-1 | at 2 years after randomization or end of trial. Worst case imputed for death and missing values | Proportion with modified Rankin score, dichotomized 0 or 1 vs 2-6.The modifed Rankin (0-6) describes the degree of functional disability. A lower score indicates less functional disability. |
Other
| Measure | Time frame |
|---|---|
| Any Stroke or Death Within 30 Days After Surgery | within 30 days after surgery |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Surgical Group Assigned to undergo extracranial-intracranial arterial bypass in addition to best current practice medical therapy | 97 |
| Non-surgical Group Receives best current practice medical therapy | 98 |
| Total | 195 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 1 |
Baseline characteristics
| Characteristic | Surgical Group | Non-surgical Group | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 21 Participants | 27 Participants | 48 Participants |
| Age, Categorical Between 18 and 65 years | 76 Participants | 71 Participants | 147 Participants |
| Age Continuous | 58 years STANDARD_DEVIATION 9 | 58 years STANDARD_DEVIATION 9 | 58 years STANDARD_DEVIATION 9 |
| Region of Enrollment Canada | 4 participants | 4 participants | 8 participants |
| Region of Enrollment United States | 93 participants | 94 participants | 187 participants |
| Sex: Female, Male Female | 28 Participants | 37 Participants | 65 Participants |
| Sex: Female, Male Male | 69 Participants | 61 Participants | 130 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 14 / 97 | 2 / 98 |
Outcome results
Primary
Surgical Group:Ipsilateral Ischemic Stroke in 2 Yrs From Randomization and All Stroke & Death Through 30d Post-surgery; Non-surgical Group:Ipsilateral Ischemic Stroke in 2 Yrs From Randomization and All Stroke & Death Through 30d Post-randomization
2 yr Kaplan-Meier estimates of the proportions.Proportions expressed as percentages for reporting purposes. Ipsilateral ischemic stroke is defined as the clinical diagnosis of a focal neurological deficit due to cerebral ischemia clinically localizable within the internal carotid artery territory distally to the symptomatic occluded internal carotid artery that lasts for more than 24 hours. All stroke is defined as the clinical diagnosis of a focal deficit due to ischemia or hemorrhage clinically localizable to the brain that lasts for more than 24 hours. Death is of any cause.
Time frame: within 2 yrs of randomization
Population: Intention to treat principle.All participants analyzed in the group to which they were originally randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Surgical Group | Surgical Group:Ipsilateral Ischemic Stroke in 2 Yrs From Randomization and All Stroke & Death Through 30d Post-surgery; Non-surgical Group:Ipsilateral Ischemic Stroke in 2 Yrs From Randomization and All Stroke & Death Through 30d Post-randomization | 21.0 percentage of participants |
| Non-surgical Group | Surgical Group:Ipsilateral Ischemic Stroke in 2 Yrs From Randomization and All Stroke & Death Through 30d Post-surgery; Non-surgical Group:Ipsilateral Ischemic Stroke in 2 Yrs From Randomization and All Stroke & Death Through 30d Post-randomization | 22.7 percentage of participants |
Comparison: Rates for each group were based on product limit estimates of 2-year rates and their standard errors. The test statistic was calculated as the difference in estimated rates divided by the standard error of that difference. The 2-sided z-statistic was compared to a standard unit normal distribution.The study was terminated early for futility after 195 of the planned 372 participants were enrolled.p-value: 0.7895% CI: [-10.4, 13.8]2-sided z-statistic
Secondary
All Stroke
2 yr Kaplan-Meier estimates of the proportions. All stroke is defined as the clinical diagnosis of a focal deficit due to ischemia or hemorrhage clinically localizable to the brain that lasts for more than 24 hours
Time frame: within 2 yrs of randomization
Population: Intention to treat principle.All participants analyzed in the group to which they were originally randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Surgical Group | All Stroke | 23.4 percentage of participants |
| Non-surgical Group | All Stroke | 26.9 percentage of participants |
Comparison: Rates for each group were based on product limit estimates of 2-year rates and their standard errors.p-value: 0.5995% CI: [-9.2, 16.1]2-sided z-statistic
Secondary
Death
2 yr Kaplan-Meier estimates of the proportions. Death of any cause
Time frame: within 2 years after randomization
Population: Intention to treat principle.All participants analyzed in the group to which they were originally randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Surgical Group | Death | 1.0 percentage of participants |
| Non-surgical Group | Death | 5.1 percentage of participants |
Comparison: Rates for each group were based on product limit estimates of 2-year rates and their standard errors. The test statistic was calculated as the difference in estimated rates divided by the standard error of that difference.p-value: 0.1395% CI: [-1.2, 9.7]2-sided z-statistic
Secondary
Disabling Stroke
2 yr Kaplan-Meier estimates of the proportions. Disabling stroke is defined as a modified Barthel Index of \<12/20 at the first scheduled return visit more than 3 months after the stroke occurred
Time frame: within two years after randomization
Population: Intention to treat principle.All participants analyzed in the group to which they were originally randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Surgical Group | Disabling Stroke | 5.9 percentage of participants |
| Non-surgical Group | Disabling Stroke | 2.4 percentage of participants |
Comparison: Rates for each group were based on product limit estimates of 2-year rates and their standard errors. The test statistic was calculated as the difference in estimated rates divided by the standard error of that difference.p-value: 0.2795% CI: [-9, 2.6]2-sided z-statistic
Secondary
Fatal Stroke
2 yr Kaplan-Meier estimates of the proportions. Fatal stroke is a stroke that in the investigator's opinion led directly to the participants death within 30 days of occurrence
Time frame: within 2 years after randomization
Population: Intention to treat principle.All participants analyzed in the group to which they were originally randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Surgical Group | Fatal Stroke | 1.0 percentage of participants |
| Non-surgical Group | Fatal Stroke | 2.4 percentage of participants |
Comparison: Rates for each group were based on product limit estimates of 2-year rates and their standard errors. The test statistic was calculated as the difference in estimated rates divided by the standard error of that difference.p-value: 0.595% CI: [-2.5, 5.2]2-sided z-statistic
Secondary
Ipsilateral Ischemic Stroke in 2 Yrs From Randomization and All Stroke & Death Through 30d Post-surgery; Non-surgical Group:Ipsilateral Ischemic Stroke in 2 Yrs From Randomization and All Stroke & Death Through 30d Post-randomization
2 yr Kaplan-Meier estimates of the proportions.Proportions expressed as percentages for reporting purposes. Ipsilateral ischemic stroke is defined as the clinical diagnosis of a focal neurological deficit due to cerebral ischemia clinically localizable within the internal carotid artery territory distally to the symptomatic occluded internal carotid artery that lasts for more than 24 hours. All stroke is defined as the clinical diagnosis of a focal deficit due to ischemia or hemorrhage clinically localizable to the brain that lasts for more than 24 hours. Death is of any cause.
Time frame: within 2 years of randomization
Population: On-treatment analysis removing four participants assigned to the surgical group who never underwent surgery and censoring on the day of surgery three participants assigned to the nonsurgical group who underwent EC-IC bypass surgery.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Surgical Group | Ipsilateral Ischemic Stroke in 2 Yrs From Randomization and All Stroke & Death Through 30d Post-surgery; Non-surgical Group:Ipsilateral Ischemic Stroke in 2 Yrs From Randomization and All Stroke & Death Through 30d Post-randomization | 20.8 percentage of participants |
| Non-surgical Group | Ipsilateral Ischemic Stroke in 2 Yrs From Randomization and All Stroke & Death Through 30d Post-surgery; Non-surgical Group:Ipsilateral Ischemic Stroke in 2 Yrs From Randomization and All Stroke & Death Through 30d Post-randomization | 22.3 percentage of participants |
Comparison: Rates for each group were based on product limit estimates of 2-year rates and their standard errors. The test statistic was calculated as the difference in estimated rates divided by the standard error of that difference.p-value: 0.8195% CI: [-10.7, 13.7]2-sided z-statistic
Secondary
Modified Barthel Index 19-20
Modified Barthel Index dichotomized 19-20 vs \<= 18. The modifed Barthel Index(0-20) describes the degree of independence in day-to-day self-care activities. A higher score indicates greater independence.
Time frame: at 2 years after randomization or end of trial. Worst case imputed for death and missing values
Population: Intention to treat principle.All participants analyzed in the group to which they were originally randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Surgical Group | Modified Barthel Index 19-20 | 70.1 percentage of participants |
| Non-surgical Group | Modified Barthel Index 19-20 | 71.4 percentage of participants |
p-value: 0.85Fisher's Exact Test
Secondary
Modified Rankin 0-1
Proportion with modified Rankin score, dichotomized 0 or 1 vs 2-6.The modifed Rankin (0-6) describes the degree of functional disability. A lower score indicates less functional disability.
Time frame: at 2 years after randomization or end of trial. Worst case imputed for death and missing values
Population: Intention to treat principle.All participants analyzed in the group to which they were originally randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Surgical Group | Modified Rankin 0-1 | 49.5 percentage of participants |
| Non-surgical Group | Modified Rankin 0-1 | 42.9 percentage of participants |
p-value: 0.4195% CI: [-20.6, 7.3]Fisher Exact
Secondary
Modified Rankin 0-2
Proportion with Modified Rankin score at 2 yrs, dichotomized 0-2 vs 3-6. The modifed Rankin (0-6) describes the degree of functional disability. A lower score indicates less functional disability.
Time frame: at 2 years after randomization or end of trial. Worst case imputed for death and missing values
Population: Intention to treat principle.All participants analyzed in the group to which they were originally randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Surgical Group | Modified Rankin 0-2 | 70.1 percentage of participants |
| Non-surgical Group | Modified Rankin 0-2 | 74.5 percentage of participants |
p-value: 0.795% CI: [-8.2, 16.9]Fisher Exact
Secondary
Summary SS-QOL Score
Summary Stroke Specific Quality of Life score (1-4) askes how self-reported overall quality of life compares with with that before stroke. A higher score indicates is better.
Time frame: at 2 years after randomization or end of trial. Worst case imputed for death and missing values
Population: Intention to treat principle.All participants analyzed in the group to which they were originally randomized.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Surgical Group | Summary SS-QOL Score | 3.82 units on a scale |
| Non-surgical Group | Summary SS-QOL Score | 3.58 units on a scale |
p-value: 0.1395% CI: [-0.54, 0.07]t-test, 2 sided
Post Hoc
Any Stroke or Death
2 yr Kaplan-Meier estimates of the proportions. Any stroke is defined as the clinical diagnosis of a focal deficit due to ischemia or hemorrhage clinically localizable to the brain that lasts for more than 24 hours. Death is of any cause.
Time frame: within 2 years after randomization
Population: Intention to treat principle.All participants analyzed in the group to which they were originally randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Surgical Group | Any Stroke or Death | 23.4 percentage of participants |
| Non-surgical Group | Any Stroke or Death | 29.9 percentage of participants |
Comparison: Rates for each group were based on product limit estimates of 2-year rates and their standard errors. The test statistic was calculated as the difference in estimated rates divided by the standard error of that difference.p-value: 0.3395% CI: [-6.5, 19.6]2-sided z-statistic
Other Pre-specified
Any Stroke or Death Within 30 Days After Surgery
Time frame: within 30 days after surgery
Population: Intention-to-treat. All assigned to undergo extracranial-intracranial arterial bypass in addition to best current practice medical therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Surgical Group | Any Stroke or Death Within 30 Days After Surgery | 14 participants |