Clinical trial NCT00059306: Secondary Prevention of Small Subcortical Strokes Trial
Official title: Secondary Prevention of Small Subcortical Strokes (SPS3) Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cerebrovascular Accident
Hypertension
Keywords: stroke
hypertension
high blood pressure
lacunar stroke
subcortical stroke
aspirin
clopidogrel
Lead sponsor: University of British Columbia
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2003-04-24
Enrollment: 3020
Sex: ALL
Minimum age (years): 30
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The goal of this study is to learn if combination antiplatelet therapy (aspirin and clopidogrel) is more effective than aspirin alone for the prevention of recurrent stroke and cognitive decline, and if intensive blood pressure control is associated with fewer recurrent strokes and cognitive decline.

On July 21, 2011 the DSMB recommended terminating the anti platelet arm of the study due to an imbalance of overall and major non-CNS hemorrhagic SAE's and total deaths in the investigational anti platelet combination of aspirin + clopidogrel and an interim statistical analysis that demonstrated futility in the investigational anti platelet arm. It was recommended that patients be continued on standard care of aspirin mono therapy until their study close-out visit. Also, recommended the continuation and completion of the plood pressure arm following the protocol.

Detailed description: Stroke is damage to the brain caused by problems in the blood vessels. Strokes often cause paralysis, loss of sensation and speech, and other problems. A lacunar or small Subcortical stroke affects the inner part of the brain causing small "pea sized" areas of damage due to blockage of small blood vessels within the brain.

This multi-center study will recruit 3000 participants (20 percent of whom will be Hispanic) to find out if using aspirin and clopidogrel is more effective than using aspirin alone to prevent recurrent stroke in patients with lacunar stroke confirmed by MRI, and if lowering a patient's blood pressure below the usual limits will also help prevent recurrent stroke and maintain thinking ability. Both aspirin and clopidogrel are widely-used for blood clotting and stroke prevention. Investigators intend to find out if using the drugs together is more effective than using aspirin alone.

Participants will be randomly assigned to one of 2 types of treatment: either aspirin alone or the combination of aspirin and clopidogrel. In addition, participants will be assigned to one of 2 groups of blood pressure control. The difference between the two groups is the target level of systolic blood pressure-either 130-149 or below 130. The goal of the blood pressure aspect of this trial is to find out if lowering blood pressure after stroke helps to prevent recurrent stroke and preserves cognition.

Eligibility criteria: INCLUSION:

Small subcortical ischemic stroke or subcortical TIA.

Inclusion criteria are based on TOAST criteria supplemented by required MRI data. All of the following criteria must be met:

* One of the lacunar stroke clinical syndromes (adapted from Fisher) lasting \> 24 hrs within the past 6 months
* Absence of signs or symptoms of cortical dysfunction such as aphasia, apraxia, agnosia, agraphia, homonymous visual field defect, etc.
* No ipsilateral cervical carotid stenosis (≥50%) by a reliable imaging modality done in an approved laboratory since the qualifying small subcortical stroke (S3), if hemispheric.
* No major-risk cardioembolic sources requiring anticoagulation or other specific therapy. Minor-risk cardioembolic sources will be permitted if anticoagulation is not prescribed by the patient's primary care physician.
* Subcortical TIA with corresponding lesion on DWI.
* MRI evidence of S3: a. Presence of an S3 (1.5 and 2 cm in diameter corresponding to the qualifying event on DWI; when TIA, ADC image must confirm lesion or T2/FLAIR (hyperintense lesions) (required for all brainstem events) OR multiple S3s on FLAIR/TI(\<1.5 cm in diameter) (hypointense lesions) b. Absence of cortical stroke and large subcortical stroke (recent or remote).

EXCLUSION:

To be eligible for entry into the study, the patient must not meet any of the criteria listed below:

* Disabling stroke (Modified Rankin Scale less than or equal to 4)
* Previous intracranial hemorrhage (excluding traumatic) or hemorrhagic stroke
* Age under 30 years
* High risk of bleeding (e.g. recurrent GI or GU bleeding, active peptic ulcer disease, etc)
* Anticipated requirement for long-term use of anticoagulants (e.g. recurrent DVT) or other antiplatelets
* Prior cortical stroke (diagnosed either clinically or by neuroimaging), or prior cortical or retinal TIA
* Prior ipsilateral carotid endarterectomy
* Impaired renal function: GFR \<40
* Intolerance or contraindications to aspirin or clopidogrel (including thrombocytopenia, prolonged INR)
* A score \< 24 (adjusted for age and education) on the Folstein Mini Mental Status Examination
* Medical contraindication to MRI
* Pregnancy or women of child-bearing potential who are not following an effective method of contraception
* Geographic or social factors making study participation impractical
* Unable or unwilling to provide informed consent
* Unlikely to be compliant with therapy/unwilling to return for frequent clinic visits
* Patients concurrently participating in another study with an investigational drug or device
* Other likely specific cause of stroke (e.g. dissection, vasculitis, prothrombotic diathesis, drug abuse)

Primary outcomes:
measure: Evidence of clinically defined ischemic stroke (focal neurological deficits persisting for more than 24 hours) confirmed by non-investigational CT or MRI
timeFrame: Mean follow up of 4 years
measure: Evidence of hemorrhagic stroke; a neurologic deficit associated with intraparenchymal or subarachnoid space lesion on CT/MRI or cerebral hemorrhage demonstrated by surgery or autopsy.
timeFrame: within mean follow-up of 4 years
Secondary outcomes:
measure: The difference in the rate of cognitive decline among SPS3 participants assigned to receive aspirin alone versus combination of aspirin and clopidogrel, assessed through repeated neuropsychological tests; and major vascular events.
timeFrame: within mean follow-up of 4 years
Other outcomes:
Locations:
city: Mobile
country: United States
facility: University of Southern Alabama Stroke Center
state: Alabama
city: Phoenix
country: United States
facility: Catholic Healthcare West
state: Arizona
city: Scottsdale
country: United States
facility: Mayo Clinic Scottsdale
state: Arizona
city: Tucson
country: United States
facility: University of Arizona, Department of Neurology
state: Arizona
city: San Diego
country: United States
facility: University of California San Diego Medical Center
state: California
city: San Francisco-Fresno
country: United States
facility: University of California San Francisco-Fresno
state: California
city: Englewood
country: United States
facility: Denver
state: Colorado
city: Melbourne
country: United States
facility: Melbourne
state: Florida
city: Miami
country: United States
facility: Miami-University of Miami, Miller School of Medicine
state: Florida
city: Atlanta
country: United States
facility: Emory University, Grady Health System
state: Georgia
city: Des Moines
country: United States
facility: Mercy Medical Center-Ruan Neurology Clinical Research
state: Iowa
city: Lexington
country: United States
facility: University of Kentucky, Aging/Stroke Program
state: Kentucky
city: Bethesda
country: United States
facility: Suburban Hospital
state: Maryland
city: Boston
country: United States
facility: Boston University
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital, Department of Neurology
state: Michigan
city: Minneapolis
country: United States
facility: Berman Center
state: Minnesota
city: Rochester
country: United States
facility: Mayo Stroke Center KA-SL-13
state: Minnesota
city: Sant Louis
country: United States
facility: University of Washington
state: Missouri
city: St. Louis
country: United States
facility: Tenet Health, St. Louis University
state: Missouri
city: St. Louis
country: United States
facility: St. John's Mercy
state: Missouri
city: Camden
country: United States
facility: Cooper University Hospital
state: New Jersey
city: Buffalo
country: United States
facility: Buffalo
state: New York
city: Haverstraw
country: United States
facility: Helen Hayes Hospital
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Rochester
country: United States
facility: Rochester General Hospital
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest University, Sciences-Neurology
state: North Carolina
city: Cleveland
country: United States
facility: Case Western
state: Ohio
city: Cleveland
country: United States
facility: Metrohealth Medical Center
state: Ohio
city: Columbus
country: United States
facility: Ohio State University, Division of Stroke
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern
state: Texas
city: Houston
country: United States
facility: Scurlock Stroke Center
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center
state: Texas
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Marshfield
country: United States
facility: Marshfield Clinic, Department of Neurology
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin-Neurology
state: Wisconsin
city: Calgary
country: Canada
facility: Calgary Health
state: Alberta
city: Vancouver
country: Canada
facility: SPS3 Coordinating Center
state: British Columbia
city: Halifax
country: Canada
facility: Halifax
state: Nova Scotia
city: Ottawa
country: Canada
facility: Ottawa Hospital General Campus
state: Ontario
city: Greenfield Park
country: Canada
facility: Greenfield Park
state: Quebec
city: Montreal
country: Canada
facility: McGill-Jewish General
state: Quebec
city: Montreal
country: Canada
facility: McGill-Montreal General
state: Quebec
city: Quebec City
country: Canada
facility: CHA-Hospital de l'Enfant-Jesus
state: Quebec
city: Santiago
country: Chile
facility: Hospital Clinico de la Universidad Católica de Chile
city: Viña del Mar
country: Chile
facility: Hospital Naval Almirante Nef, 'Subida Alessandri s/n, Hall A, Oficina 9
city: Guayaquil
country: Ecuador
facility: Hospital-Clinica Kennedy
city: Monterrey
country: Mexico
facility: Hospital de La Universidad Autonoma de Nuevo Leon
state: Nuevo Leon
city: Guadalajara
country: Mexico
facility: Antiguo Hospital Civil de Guadalajara
city: Mexico City
country: Mexico
facility: Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zuibrán
city: Mexico City
country: Mexico
facility: Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez
city: Bellavista-Callao
country: Peru
facility: Hospital Sabogal Essalud-Unidad de Investigacion
state: Lima
city: Badalona
country: Spain
facility: Hosp. Universitario Germans Trias I Pujol
city: Barcelona
country: Spain
facility: Hospital Del Mar, Passeig Marítim 25-29
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu I Sant Pau, c/Sant Antoni Maria Claret, 167
city: Barcelona
country: Spain
facility: Hospital del Sagrat Cor. Quinta de Salut I'Alianca, c/Viladomat 288
city: Barcelona
country: Spain
facility: Hosp. Parc Tauli de Sabadell
city: Girona
country: Spain
facility: Hosp. de Girona Dr. Josep Trueta
city: Madrid
country: Spain
facility: Hospital La Paz
city: Santiago de Compostela
country: Spain
facility: Universidad de Santiago de Compostela, Facultad de Medicina y Odontologia
Study officials:
affiliation: University of British Columbia
name: Oscar Benavente, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: McMaster University
name: Robert Hart, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Saiz LC, Gorricho J, Garjon J, Celaya MC, Erviti J, Leache L. Blood pressure targets for the treatment of people with hypertension and cardiovascular disease. Cochrane Database Syst Rev. 2022 Nov 18;11(11):CD010315. doi: 10.1002/14651858.CD010315.pub5.
citation: Natale P, Palmer SC, Saglimbene VM, Ruospo M, Razavian M, Craig JC, Jardine MJ, Webster AC, Strippoli GF. Antiplatelet agents for chronic kidney disease. Cochrane Database Syst Rev. 2022 Feb 28;2(2):CD008834. doi: 10.1002/14651858.CD008834.pub4.
citation: Shihab S, Boucher RE, Abraham N, Wei G, Beddhu S. Influence of Baseline Diastolic Blood Pressure on the Effects of Intensive Systolic Blood Pressure Lowering on the Risk of Stroke. Hypertension. 2022 Apr;79(4):785-793. doi: 10.1161/HYPERTENSIONAHA.121.18172. Epub 2022 Feb 4.
citation: Cukierman-Yaffe T, McClure LA, Risoli T, Bosch J, Sharma M, Gerstein HC, Benavente O. The Relationship Between Glucose Control and Cognitive Function in People With Diabetes After a Lacunar Stroke. J Clin Endocrinol Metab. 2021 Mar 25;106(4):e1521-e1528. doi: 10.1210/clinem/dgab022.
citation: Saiz LC, Gorricho J, Garjon J, Celaya MC, Erviti J, Leache L. Blood pressure targets for the treatment of people with hypertension and cardiovascular disease. Cochrane Database Syst Rev. 2020 Sep 9;9(9):CD010315. doi: 10.1002/14651858.CD010315.pub4.
citation: Blum MR, Scherzer R, Ikeme JC, Benavente OR, McClure LA, Peralta CA, Odden MC. Functional health and white matter hyperintensities as effect modifiers of blood pressure-lowering on cognitive function and vascular events in older Secondary Prevention of Small Subcortical Strokes trial participants. J Hypertens. 2020 Aug;38(8):1578-1585. doi: 10.1097/HJH.0000000000002440.
citation: Agarwal A, Cheung AK, Ma J, Cho M, Li M. Effect of Baseline Kidney Function on the Risk of Recurrent Stroke and on Effects of Intensive Blood Pressure Control in Patients With Previous Lacunar Stroke: A Post Hoc Analysis of the SPS3 Trial (Secondary Prevention of Small Subcortical Strokes). J Am Heart Assoc. 2019 Aug 20;8(16):e013098. doi: 10.1161/JAHA.119.013098. Epub 2019 Aug 19.
citation: Ikeme JC, Pergola PE, Scherzer R, Shlipak MG, Catanese L, McClure LA, Benavente OR, Peralta CA. Cerebral White Matter Hyperintensities, Kidney Function Decline, and Recurrent Stroke After Intensive Blood Pressure Lowering: Results From the Secondary Prevention of Small Subcortical Strokes ( SPS 3) Trial. J Am Heart Assoc. 2019 Feb 5;8(3):e010091. doi: 10.1161/JAHA.118.010091.
citation: Magvanjav O, McDonough CW, Gong Y, McClure LA, Talbert RL, Horenstein RB, Shuldiner AR, Benavente OR, Mitchell BD, Johnson JA; NINDS SiGN (Stroke Genetics Network). Pharmacogenetic Associations of beta1-Adrenergic Receptor Polymorphisms With Cardiovascular Outcomes in the SPS3 Trial (Secondary Prevention of Small Subcortical Strokes). Stroke. 2017 May;48(5):1337-1343. doi: 10.1161/STROKEAHA.116.015936. Epub 2017 Mar 28.
citation: Wilson LK, Pearce LA, Arauz A, Anderson DC, Tapia J, Bazan C, Benavente OR, Field TS; SPS3 Investigators. Morphological classification of penetrating artery pontine infarcts and association with risk factors and prognosis: The SPS3 trial. Int J Stroke. 2016 Jun;11(4):412-9. doi: 10.1177/1747493016637366. Epub 2016 Mar 8.
citation: Boehme AK, McClure LA, Zhang Y, Luna JM, Del Brutto OH, Benavente OR, Elkind MS. Inflammatory Markers and Outcomes After Lacunar Stroke: Levels of Inflammatory Markers in Treatment of Stroke Study. Stroke. 2016 Mar;47(3):659-67. doi: 10.1161/STROKEAHA.115.012166.
citation: Peralta CA, McClure LA, Scherzer R, Odden MC, White CL, Shlipak M, Benavente O, Pergola P. Effect of Intensive Versus Usual Blood Pressure Control on Kidney Function Among Individuals With Prior Lacunar Stroke: A Post Hoc Analysis of the Secondary Prevention of Small Subcortical Strokes (SPS3) Randomized Trial. Circulation. 2016 Feb 9;133(6):584-91. doi: 10.1161/CIRCULATIONAHA.115.019657. Epub 2016 Jan 13.
citation: Odden MC, McClure LA, Sawaya BP, White CL, Peralta CA, Field TS, Hart RG, Benavente OR, Pergola PE. Achieved Blood Pressure and Outcomes in the Secondary Prevention of Small Subcortical Strokes Trial. Hypertension. 2016 Jan;67(1):63-9. doi: 10.1161/HYPERTENSIONAHA.115.06480. Epub 2015 Nov 9.
citation: McDonough CW, McClure LA, Mitchell BD, Gong Y, Horenstein RB, Lewis JP, Field TS, Talbert RL, Benavente OR, Johnson JA, Shuldiner AR. CYP2C19 metabolizer status and clopidogrel efficacy in the Secondary Prevention of Small Subcortical Strokes (SPS3) study. J Am Heart Assoc. 2015 May 27;4(6):e001652. doi: 10.1161/JAHA.114.001652.
citation: Pearce LA, McClure LA, Anderson DC, Jacova C, Sharma M, Hart RG, Benavente OR; SPS3 Investigators. Effects of long-term blood pressure lowering and dual antiplatelet treatment on cognitive function in patients with recent lacunar stroke: a secondary analysis from the SPS3 randomised trial. Lancet Neurol. 2014 Dec;13(12):1177-85. doi: 10.1016/S1474-4422(14)70224-8. Epub 2014 Oct 23.
citation: Field TS, McClure LA, White CL, Pergola PE, Hart RG, Benavente OR, Hill MD; SPS3 Investigators. Should Blood Pressure Targets After Lacunar Stroke Vary by Body Size? The SPS3 Trial. Am J Hypertens. 2015 Jun;28(6):756-64. doi: 10.1093/ajh/hpu228. Epub 2014 Dec 1.
citation: Asdaghi N, Pearce LA, Nakajima M, Field TS, Bazan C, Cermeno F, McClure LA, Anderson DC, Hart RG, Benavente OR; SPS3 Investigators. Clinical correlates of infarct shape and volume in lacunar strokes: the Secondary Prevention of Small Subcortical Strokes trial. Stroke. 2014 Oct;45(10):2952-8. doi: 10.1161/STROKEAHA.114.005211. Epub 2014 Sep 4.
citation: Sharma M, Pearce LA, Benavente OR, Anderson DC, Connolly SJ, Palacio S, Coffey CS, Hart RG. Predictors of mortality in patients with lacunar stroke in the secondary prevention of small subcortical strokes trial. Stroke. 2014 Oct;45(10):2989-94. doi: 10.1161/STROKEAHA.114.005789. Epub 2014 Aug 26.
citation: Palacio S, McClure LA, Benavente OR, Bazan C 3rd, Pergola P, Hart RG. Lacunar strokes in patients with diabetes mellitus: risk factors, infarct location, and prognosis: the secondary prevention of small subcortical strokes study. Stroke. 2014 Sep;45(9):2689-94. doi: 10.1161/STROKEAHA.114.005018. Epub 2014 Jul 17.
citation: Benavente OR, Pearce LA, Bazan C, Roldan AM, Catanese L, Bhat Livezey VM, Vidal-Pergola G, McClure LA, Hart RG; SPS3 Investigators. Clinical-MRI correlations in a multiethnic cohort with recent lacunar stroke: the SPS3 trial. Int J Stroke. 2014 Dec;9(8):1057-64. doi: 10.1111/ijs.12282. Epub 2014 May 27.
citation: Lewis BL, Pearce LA, Field TS, White CL, Benavente OR; SPS3 Investigators. The relevance of living supports on antiplatelet adherence and trial participation: the SPS3 trial. Int J Stroke. 2014 Jun;9(4):443-8. doi: 10.1111/ijs.12267. Epub 2014 Mar 24.
citation: Elkind MS, Luna JM, McClure LA, Zhang Y, Coffey CS, Roldan A, Del Brutto OH, Pretell EJ, Pettigrew LC, Meyer BC, Tapia J, White C, Benavente OR; LIMITS Investigators. C-reactive protein as a prognostic marker after lacunar stroke: levels of inflammatory markers in the treatment of stroke study. Stroke. 2014 Mar;45(3):707-16. doi: 10.1161/STROKEAHA.113.004562. Epub 2014 Feb 12.
citation: Dhamoon MS, McClure LA, White CL, Lau H, Benavente O, Elkind MS. Quality of life after lacunar stroke: the Secondary Prevention of Small Subcortical Strokes study. J Stroke Cerebrovasc Dis. 2014 May-Jun;23(5):1131-7. doi: 10.1016/j.jstrokecerebrovasdis.2013.09.029. Epub 2013 Oct 28.
citation: White CL, Pergola PE, Szychowski JM, Talbert R, Cervantes-Arriaga A, Clark HD, Del Brutto OH, Godoy IE, Hill MD, Pelegri A, Sussman CR, Taylor AA, Valdivia J, Anderson DC, Conwit R, Benavente OR; SPS3 Investigators. Blood pressure after recent stroke: baseline findings from the secondary prevention of small subcortical strokes trial. Am J Hypertens. 2013 Sep;26(9):1114-22. doi: 10.1093/ajh/hpt076. Epub 2013 Jun 4.
citation: SPS3 Study Group; Benavente OR, Coffey CS, Conwit R, Hart RG, McClure LA, Pearce LA, Pergola PE, Szychowski JM. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet. 2013 Aug 10;382(9891):507-15. doi: 10.1016/S0140-6736(13)60852-1. Epub 2013 May 29.
citation: Jacova C, Pearce LA, Costello R, McClure LA, Holliday SL, Hart RG, Benavente OR. Cognitive impairment in lacunar strokes: the SPS3 trial. Ann Neurol. 2012 Sep;72(3):351-62. doi: 10.1002/ana.23733.
citation: SPS3 Investigators; Benavente OR, Hart RG, McClure LA, Szychowski JM, Coffey CS, Pearce LA. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med. 2012 Aug 30;367(9):817-25. doi: 10.1056/NEJMoa1204133.
citation: Palacio S, Hart RG, Pearce LA, Benavente OR. Effect of addition of clopidogrel to aspirin on mortality: systematic review of randomized trials. Stroke. 2012 Aug;43(8):2157-62. doi: 10.1161/STROKEAHA.112.656173.
citation: McClure LA, Szychowski JM, Benavente O, Coffey CS. Sample size re-estimation in an on-going NIH-sponsored clinical trial: the secondary prevention of small subcortical strokes experience. Contemp Clin Trials. 2012 Sep;33(5):1088-93. doi: 10.1016/j.cct.2012.06.007. Epub 2012 Jun 30.
citation: Graves JW, White CL, Szychowski JM, Pergola PE, Benavente OR, Coffey CS, Hornung LN, Hart RG; SPS3 Study Investigators. Predictors of lowering SBP to assigned targets at 12 months in the Secondary Prevention of Small Subcortical Strokes study. J Hypertens. 2012 Jun;30(6):1233-40. doi: 10.1097/HJH.0b013e328353968d.
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: Benavente OR, White CL, Pearce L, Pergola P, Roldan A, Benavente MF, Coffey C, McClure LA, Szychowski JM, Conwit R, Heberling PA, Howard G, Bazan C, Vidal-Pergola G, Talbert R, Hart RG; SPS3 Investigators. The Secondary Prevention of Small Subcortical Strokes (SPS3) study. Int J Stroke. 2011 Apr;6(2):164-75. doi: 10.1111/j.1747-4949.2010.00573.x. Epub 2011 Jan 26.
citation: Elkind MS, Luna JM, Coffey CS, McClure LA, Liu KM, Spitalnik S, Paik MC, Roldan A, White C, Hart R, Benavente O. The Levels of Inflammatory Markers in the Treatment of Stroke study (LIMITS): inflammatory biomarkers as risk predictors after lacunar stroke. Int J Stroke. 2010 Apr;5(2):117-25. doi: 10.1111/j.1747-4949.2010.00420.x.