Clinical trial NCT00576693: Stenting vs. Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis
Official title: Stenting vs. Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Ischemic Stroke
Keywords: ischemic stroke
intracranial stenting
vascular risk factor management
Lead sponsor: Medical University of South Carolina
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2007-12-19
Enrollment: 451
Sex: ALL
Minimum age (years): 30
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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

Primary outcomes:
measure: Any Stroke or Death Within 30 Days of Enrollment or Any Revascularization Procedure OR an Ischemic Stroke in the Territory of the Symptomatic Intracranial Artery Beyond 30 Days After Enrollment.
timeFrame: Mean length of follow-up was 2.4 years
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: UAB Medical Center
state: Alabama
city: Phoenix
country: United States
facility: Barrow Neurological Institute - St. Joseph's Hospital and Medical Center
state: Arizona
city: Phoenix
country: United States
facility: Mayo
state: Arizona
city: Glendale
country: United States
facility: Glendale Adventist
state: California
city: Los Angeles
country: United States
facility: Cedars Sinai
state: California
city: Los Angeles
country: United States
facility: UCLA
state: California
city: San Francisco
country: United States
facility: UCSF
state: California
city: Washington
country: United States
facility: Washington Hospital
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida - Shands
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Winter Park
country: United States
facility: Florida Hospital
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Winfield
country: United States
facility: Central DuPage Hospital
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Medical Center
state: Michigan
city: Southfield
country: United States
facility: Providence St. John
state: Michigan
city: Jackson
country: United States
facility: University of Mississippi
state: Mississippi
city: Buffalo
country: United States
facility: University of Buffalo
state: New York
city: New York
country: United States
facility: NYU Medical Center
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Cornell Medical College
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University Medical Center
state: New York
city: Charlotte
country: United States
facility: Carolinas Medical Center
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Greensboro
country: United States
facility: Moses Cone Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Forsyth Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals Case Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: Riverside Methodist
state: Ohio
city: Portland
country: United States
facility: Oregon Health Sciences University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Chattanooga
country: United States
facility: Erlanger Medical Center
state: Tennessee
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Dallas
country: United States
facility: UT Southwestern
state: Texas
city: Houston
country: United States
facility: Baylor St. Luke's
state: Texas
city: Houston
country: United States
facility: Methodist Hospital
state: Texas
city: Temple
country: United States
facility: Scott & White - Texas A&M
state: Texas
city: Falls Church
country: United States
facility: Inova Fairfax Hospital
state: Virginia
city: Norfolk
country: United States
facility: Sentera
state: Virginia
city: Spokane
country: United States
facility: Sacred Heart Medical Center
state: Washington
city: Tacoma
country: United States
facility: MultiCare
state: Washington
city: Morgantown
country: United States
facility: West Virginia University
state: West Virginia
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Medical University of South Carolina
name: Marc I Chimowitz, MBChB
role: PRINCIPAL_INVESTIGATOR
References:
citation: Derdeyn CP, Fiorella D, Lynn MJ, Barnwell SL, Zaidat OO, Meyers PM, Gobin YP, Dion J, Lane BF, Turan TN, Janis LS, Chimowitz MI; SAMMPRIS Trial Investigators. Impact of operator and site experience on outcomes after angioplasty and stenting in the SAMMPRIS trial. J Neurointerv Surg. 2013 Nov;5(6):528-33. doi: 10.1136/neurintsurg-2012-010504. Epub 2012 Sep 12.
citation: Turan TN, Lynn MJ, Nizam A, Lane B, Egan BM, Le NA, Lopes-Virella MF, Hermayer KL, Benavente O, White CL, Brown WV, Caskey MF, Steiner MR, Vilardo N, Stufflebean A, Derdeyn CP, Fiorella D, Janis S, Chimowitz MI; SAMMPRIS Investigators. Rationale, design, and implementation of aggressive risk factor management in the Stenting and Aggressive Medical Management for Prevention of Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial. Circ Cardiovasc Qual Outcomes. 2012 Sep 1;5(5):e51-60. doi: 10.1161/CIRCOUTCOMES.112.966911. No abstract available.
citation: Fiorella D, Derdeyn CP, Lynn MJ, Barnwell SL, Hoh BL, Levy EI, Harrigan MR, Klucznik RP, McDougall CG, Pride GL Jr, Zaidat OO, Lutsep HL, Waters MF, Hourihane JM, Alexandrov AV, Chiu D, Clark JM, Johnson MD, Torbey MT, Rumboldt Z, Cloft HJ, Turan TN, Lane BF, Janis LS, Chimowitz MI; SAMMPRIS Trial Investigators. Detailed analysis of periprocedural strokes in patients undergoing intracranial stenting in Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS). Stroke. 2012 Oct;43(10):2682-8. doi: 10.1161/STROKEAHA.112.661173. Epub 2012 Sep 13.
citation: Chimowitz MI, Lynn MJ, Derdeyn CP, Turan TN, Fiorella D, Lane BF, Janis LS, Lutsep HL, Barnwell SL, Waters MF, Hoh BL, Hourihane JM, Levy EI, Alexandrov AV, Harrigan MR, Chiu D, Klucznik RP, Clark JM, McDougall CG, Johnson MD, Pride GL Jr, Torbey MT, Zaidat OO, Rumboldt Z, Cloft HJ; SAMMPRIS Trial Investigators. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med. 2011 Sep 15;365(11):993-1003. doi: 10.1056/NEJMoa1105335. Epub 2011 Sep 7.
citation: Derdeyn CP, Chimowitz MI, Lynn MJ, Fiorella D, Turan TN, Janis LS, Montgomery J, Nizam A, Lane BF, Lutsep HL, Barnwell SL, Waters MF, Hoh BL, Hourihane JM, Levy EI, Alexandrov AV, Harrigan MR, Chiu D, Klucznik RP, Clark JM, McDougall CG, Johnson MD, Pride GL Jr, Lynch JR, Zaidat OO, Rumboldt Z, Cloft HJ; Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis Trial Investigators. Aggressive medical treatment with or without stenting in high-risk patients with intracranial artery stenosis (SAMMPRIS): the final results of a randomised trial. Lancet. 2014 Jan 25;383(9914):333-41. doi: 10.1016/S0140-6736(13)62038-3. Epub 2013 Oct 26.
citation: Yaghi S, Khatri P, de Havenon A, Yeatts S, Chang AD, Cutting S, Mac Grory B, Burton T, Jayaraman MV, McTaggart RA, Fiorella D, Derdeyn C, Zaidat OO, Dehkharghani S, Amin-Hanjani S, Furie K, Prahbakaran S, Liebeskind D. Peri-procedural stroke or death in stenting of symptomatic severe intracranial stenosis. J Neurointerv Surg. 2020 Apr;12(4):374-379. doi: 10.1136/neurintsurg-2019-015225. Epub 2019 Sep 4.
citation: Wabnitz AM, Derdeyn CP, Fiorella DJ, Lynn MJ, Cotsonis GA, Liebeskind DS, Waters MF, Lutsep H, Lopez-Cancio E, Turan TN, Montgomery J, Janis LS, Lane B, Chimowitz MI; SAMMPRIS Investigators. Hemodynamic Markers in the Anterior Circulation as Predictors of Recurrent Stroke in Patients With Intracranial Stenosis. Stroke. 2019 Jan;50(1):143-147. doi: 10.1161/STROKEAHA.118.020840. Epub 2018 Dec 11.
citation: Derdeyn CP, Fiorella D, Lynn MJ, Turan TN, Cotsonis GA, Lane BF, Montgomery J, Janis LS, Chimowitz MI; SAMMPRIS Investigators. Nonprocedural Symptomatic Infarction and In-Stent Restenosis After Intracranial Angioplasty and Stenting in the SAMMPRIS Trial (Stenting and Aggressive Medical Management for the Prevention of Recurrent Stroke in Intracranial Stenosis). Stroke. 2017 Jun;48(6):1501-1506. doi: 10.1161/STROKEAHA.116.014537. Epub 2017 Apr 28.
citation: Turan TN, Nizam A, Lynn MJ, Egan BM, Le NA, Lopes-Virella MF, Hermayer KL, Harrell J, Derdeyn CP, Fiorella D, Janis LS, Lane B, Montgomery J, Chimowitz MI. Relationship between risk factor control and vascular events in the SAMMPRIS trial. Neurology. 2017 Jan 24;88(4):379-385. doi: 10.1212/WNL.0000000000003534. Epub 2016 Dec 21.
citation: Waters MF, Hoh BL, Lynn MJ, Kwon HM, Turan TN, Derdeyn CP, Fiorella D, Khanna A, Sheehan TO, Lane BF, Janis S, Montgomery J, Chimowitz MI; Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) Trial Investigators. Factors Associated With Recurrent Ischemic Stroke in the Medical Group of the SAMMPRIS Trial. JAMA Neurol. 2016 Mar;73(3):308-15. doi: 10.1001/jamaneurol.2015.4315.
citation: Kwon HM, Lynn MJ, Turan TN, Derdeyn CP, Fiorella D, Lane BF, Montgomery J, Janis LS, Rumboldt Z, Chimowitz MI; SAMMPRIS Investigators. Frequency, Risk Factors, and Outcome of Coexistent Small Vessel Disease and Intracranial Arterial Stenosis: Results From the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) Trial. JAMA Neurol. 2016 Jan;73(1):36-42. doi: 10.1001/jamaneurol.2015.3145.
citation: Lutsep HL, Lynn MJ, Cotsonis GA, Derdeyn CP, Turan TN, Fiorella D, Janis LS, Lane BF, Montgomery J, Chimowitz MI; SAMMPRIS Investigators. Does the Stenting Versus Aggressive Medical Therapy Trial Support Stenting for Subgroups With Intracranial Stenosis? Stroke. 2015 Nov;46(11):3282-4. doi: 10.1161/STROKEAHA.115.009846. Epub 2015 Sep 17.
citation: Chaturvedi S, Turan TN, Lynn MJ, Derdeyn CP, Fiorella D, Janis LS, Chimowitz MI; SAMMPRIS Trial Investigators. Do Patient Characteristics Explain the Differences in Outcome Between Medically Treated Patients in SAMMPRIS and WASID? Stroke. 2015 Sep;46(9):2562-7. doi: 10.1161/STROKEAHA.115.009656. Epub 2015 Aug 6.
citation: Lutsep HL, Barnwell SL, Larsen DT, Lynn MJ, Hong M, Turan TN, Derdeyn CP, Fiorella D, Janis LS, Chimowitz MI; SAMMPRIS Investigators. Outcome in patients previously on antithrombotic therapy in the SAMMPRIS trial: subgroup analysis. Stroke. 2015 Mar;46(3):775-9. doi: 10.1161/STROKEAHA.114.007752. Epub 2015 Jan 15.