Stenting vs. Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis

PRIMARY HYPOTHESIS:

Compared with intensive medical therapy alone, intracranial angioplasty and stenting combined with intensive medical therapy will decrease the risk of the primary endpoint by 35% over a mean follow-up of two years in high-risk patients patients with 70% - 99% intracranial stenosis who had a transient ischemic attack (TIA) or stroke within 30 days prior to enrollment) with symptomatic stenosis of a major intracranial artery.

SUMMARY:

The best treatment for prevention of another stroke or TIA in patients with narrowing of one of the arteries in the brain is uncertain. A common treatment is the use of anti-clotting medications to prevent blood clots from forming in the narrowed vessel. There are a variety of medicines used for this purpose. These medications are usually taken for the rest of a patient's life.

However, a treatment that has been used successfully together with anti-clotting medications in patients with narrowing of the blood vessels of the heart is now being studied in the blood vessels of the brain. This treatment is called stenting.

Recent research has also indicated a benefit in prevention of recurring stroke by Intensive Medical Therapy, which is defined as treating risk factors for stroke like high blood pressure, elevated LDL (low density lipids - the "bad" form of cholesterol) and diabetes. The purpose of this study is to compare the safety and effectiveness of either Intensive Medical Therapy PLUS Stenting or Intensive Medical Therapy ONLY in preventing stroke, heart attacks or death.

The study will enroll patients over a 5 year period. Each participant will be involved in the study for a minimum of 1 year and a maximum of 3 years.

Fifty different medical centers in the United States are part of this study. Both the Clinical Coordinating Center and the Statistical Coordinating Center for the entire study will be located at Emory University.

This will be an investigator initiated and designed Phase III multicenter trial in which patients with TIA or non-disabling stroke within 30 days prior to enrollment that is caused by 70% - 99% stenosis of a major intracranial artery (MCA, carotid, vertebral, or basilar) will be randomized (1:1) at approximately 50 sites to:

intensive medical therapy alone (aspirin 325 mg / day for entire follow-up, clopidogrel 75mg per day for 90 days after enrollment unless cardiologist recommends continuing clopidogrel beyond 90 days for a cardiac indication, and aggressive risk factor management primarily targeting blood pressure \< 140 / 90 mm Hg (\< 130 / 80 if diabetic) and LDL \< 70 mg / dl)

OR

intracranial angioplasty and stenting using the Gateway balloon and Wingspan self-expanding nitinol stent (or any future FDA approved iterations of the balloon, stent, or the delivery systems) plus intensive medical therapy (aspirin 325 mg / day for entire follow-up, clopidogrel 75mg per day for 90 days after enrollment unless cardiologist recommends continuing clopidogrel beyond 90 days for a cardiac indication, and aggressive risk factor management primarily targeting blood pressure \< 140 / 90 mm Hg (\< 130 / 80 if diabetic) and LDL \< 70 mg / dl).

Risk factor management will be performed by the study neurologist at each site who will be assisted by an innovative, evidence-based, educational, lifestyle modification program (INTERxVENT) that will be administered at regularly scheduled times to all patients throughout the study.

All patients enrolled in the trial will be followed until the first of the following: 90 days after a primary endpoint, death, or the close-out visit in the trial, which will occur within a window from 60 days before March 31, 2012 to 30 days after March 31, 2013. Patients who do not die or have a primary endpoint during follow-up will be followed for 2-4.5 years.

Eligibility Criteria:
INCLUSION CRITERIA

1. Transient ischemic attack (TIA) or non-severe stroke within 30 days of enrollment attributed to 70-99% stenosis of a major intracranial artery (carotid artery, MCA stem (M1), vertebral artery, or basilar artery)

   • may be diagnosed byTranscranial Doppler (TCD), Magnetic Resonance Angiogram (MRA), or computed tomography angiography (CTA) to qualify for angiogram performed as part of the study protocol but must be confirmed by catheter angiography for enrollment in the trial
2. Modified Rankin score of ≤ 3
3. Target area of stenosis in an intracranial artery that has a normal diameter of 2.00 mm to 4.50 mm
4. Target area of stenosis is less than or equal to 14 mm in length
5. Age ≥ 30 years and ≤ 80 years.

   • Patients 30-49 years are required to meet at least one additional criteria (i-vi) provided in the table below to qualify for the study. This additional requirement is to increase the likelihood that the symptomatic intracranial stenosis in patients 30-49 years is atherosclerotic.

   i. insulin dependent diabetes for at least 15 years ii. at least 2 of the following atherosclerotic risk factors: hypertension (BP \> 140/90 or on antihypertensive therapy); dyslipidemia (LDL \> 130 mg /dl or HDL \< 40 mg/dl or fasting triglycerides \> 150 mg/dl or on lipid lowering therapy); smoking; non-insulin dependent diabetes or insulin dependent diabetes of less than 15 years duration; family history of any of the following: myocardial infarction, coronary artery bypass, coronary angioplasty or stenting, stroke, carotid endarterectomy or stenting, peripheral vascular surgery in parent or sibling who was \< 55 years of age for men or \< 65 for women at the time of the event ii. history of any of the following: myocardial infarction, coronary artery bypass, coronary angioplasty or stenting, carotid endarterectomy or stenting, or peripheral vascular surgery for atherosclerotic disease iv. any stenosis of an extracranial carotid or vertebral artery, another intracranial artery, subclavian artery, coronary artery, iliac or femoral artery, other lower or upper extremity artery, mesenteric artery, or renal artery that was documented by non-invasive vascular imaging or catheter angiography and is considered atherosclerotic v. aortic arch atheroma documented by non-invasive vascular imaging or catheter angiography vi. any aortic aneurysm documented by non-invasive vascular imaging or catheter angiography that is considered atherosclerotic
6. Negative pregnancy test in a female who has had any menses in the last 18 months
7. Patient is willing and able to return for all follow-up visits required by the protocol
8. Patient is available by phone
9. Patient understands the purpose and requirements of the study, can make him/herself understood, and has provided informed consent

EXCLUSION CRITERIA

1. Tandem extracranial or intracranial stenosis (70%-99%) or occlusion that is proximal or distal to the target intracranial lesion (NOTE: an exception is allowed if the occlusion involves a single vertebral artery proximal to a symptomatic basilar artery stenosis and the contralateral vertebral artery is supplying the basilar artery)
2. Bilateral intracranial vertebral artery stenosis of 70%-99% and uncertainty about which artery is symptomatic (e.g. if patient has pontine, midbrain, or temporal - occipital symptoms)
3. Stenting, angioplasty, or endarterectomy of an extracranial (carotid or vertebral artery) or intracranial artery within 30 days prior to expected enrollment date
4. Previous treatment of target lesion with a stent, angioplasty, or other mechanical device, or plan to perform staged angioplasty followed by stenting of target lesion
5. Plan to perform concomitant angioplasty or stenting of an extracranial vessel tandem to an intracranial stenosis
6. Presence of intraluminal thrombus proximal to or at the target lesion
7. Any aneurysm proximal to or distal to stenotic intracranial artery
8. Intracranial tumor (except meningioma) or any intracranial vascular malformation
9. CT or angiographic evidence of severe calcification at target lesion
10. Thrombolytic therapy within 24 hours prior to enrollment
11. Progressive neurological signs within 24 hours prior to enrollment
12. Brain infarct within previous 30 days of enrollment that is of sufficient size (\> 5 cms) to be at risk of hemorrhagic conversion during or after stenting
13. Any hemorrhagic infarct within 14 days prior to enrollment
14. Any hemorrhagic infarct within 15 - 30 days that is associated with mass effect
15. Any history of a primary intracerebral (parenchymal) hemorrhage (ICH)
16. Any other intracranial hemorrhage (subarachnoid, subdural, epidural) within 30 days
17. Any untreated chronic subdural hematoma of greater than 5 mm in thickness
18. Intracranial arterial stenosis due to arterial dissection, Moya Moya disease; any known vasculitic disease; herpes zoster, varicella zoster or other viral vasculopathy; neurosyphilis; any other intracranial infection; any intracranial stenosis associated with Cerebrospinal fluid (CSF) pleocytosis; radiation induced vasculopathy; fibromuscular dysplasia; sickle cell disease; neurofibromatosis; benign angiopathy of central nervous system; post-partum angiopathy; suspected vasospastic process, suspected recanalized embolus
19. Presence of any of the following unequivocal cardiac sources of embolism: chronic or paroxysmal atrial fibrillation, mitral stenosis, mechanical valve, endocarditis, intracardiac clot or vegetation, myocardial infarction within three months, dilated cardiomyopathy, left atrial spontaneous echo contrast, ejection fraction less than 30%
20. Known allergy or contraindication to aspirin, clopidogrel, heparin, nitinol, local or general anesthesia
21. History of life-threatening allergy to contrast dye. If not life threatening and can be effectively pretreated, patient can be enrolled at physician's discretion
22. Active peptic ulcer disease, major systemic hemorrhage within 30 days, active bleeding diathesis, platelets \< 100,000, hematocrit \< 30, International normalized ratio (INR) \> 1.5, clotting factor abnormality that increases the risk of bleeding, current alcohol or substance abuse, uncontrolled severe hypertension (systolic pressure \> 180 mm Hg or diastolic pressure \> 115 mm Hg), severe liver impairment Aspartate Transaminase (AST) or Alanine transaminase (ALT) \> 3 x normal, cirrhosis, creatinine \> 3.0 (unless on dialysis)
23. Major surgery (including open femoral, aortic, or carotid surgery) within previous 30 days or planned in the next 90 days after enrollment
24. Indication for warfarin or heparin beyond enrollment (NOTE: exceptions allowed for use of systemic heparin during stenting procedure or subcutaneous heparin for deep vein thrombosis (DVT) prophylaxis while hospitalized)
25. Severe neurological deficit that renders the patient incapable of living independently
26. Dementia or psychiatric problem that prevents the patient from following an outpatient program reliably
27. Co-morbid conditions that may limit survival to less than 3 years
28. Pregnancy or of childbearing potential and unwilling to use contraception for the duration of this study
29. Enrollment in another study that would conflict with the current study