Clinical trial NCT03192215: AtRial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke
Official title: AtRial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Stroke
Keywords: Atrial Cardiopathy
Cryptogenic stroke
Ischemic stroke
Apixaban
Aspirin
Lead sponsor: Columbia University
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
name: University of Cincinnati
name: Medical University of South Carolina
name: Bristol-Myers Squibb
name: Pfizer
name: Roche Pharma AG
name: Weill Medical College of Cornell University
name: University of Washington
First posted: 2017-06-20
Enrollment: 1015
Sex: ALL
Minimum age (years): 45
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Active treatment will be either apixaban 5 mg or aspirin 81 mg. An adjusted dose of apixaban 2.5 mg will be used for subjects with at least two of the following: age greater than or equal to 80 years, body weight less than or equal to 60 kg, or known serum creatinine greater than or equal to 1.5 mg/dL. There will be six possible study tablets: apixaban 5 mg (regular dose), apixaban 2.5 mg (adjusted dose), apixaban 5 mg placebo, apixaban 2.5 mg placebo, aspirin 81 mg, and aspirin placebo.

All subjects will be randomized to receive active treatment with either active apixaban or active aspirin. Study treatments will be supplied in a double-dummy fashion as apixaban 5 mg (2.5 mg for the adjusted dose) or matching placebo, and aspirin 81 mg or matching placebo.
Primary purpose: PREVENTION

Brief summary: Objectives

* Primary: To test the hypothesis that apixaban is superior to aspirin for the prevention of recurrent stroke in patients with cryptogenic ischemic stroke and atrial cardiopathy.
* Secondary: To test the hypothesis that the relative efficacy of apixaban over aspirin increases with the severity of atrial cardiopathy.

Detailed description: ARCADIA is a multicenter, biomarker-driven, randomized, double-blind, active-control, phase 3 clinical trial of apixaban versus aspirin in patients who have evidence of atrial cardiopathy and a recent stroke of unknown cause. Eleven hundred subjects will be recruited over 2.5 years at up to 200 sites in and out of the NINDS StrokeNet consortium. Subjects will be followed for a minimum of 1.5 years and a maximum of 7 years for the primary efficacy outcome of recurrent stroke and the primary safety outcomes of symptomatic intracranial hemorrhage and major hemorrhage other than intracranial hemorrhage.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 45 years.
* Clinical diagnosis of ischemic stroke + brain imaging to rule out hemorrhagic stroke.
* Modified Rankin Scale (MRS) score ≤ 4.
* Ability to be randomized within 3 to 180 days after stroke onset.
* ESUS, defined as all of the following:

  * Stroke detected by CT or MRI that is not lacunar. Lacunar is defined as a subcortical (this includes pons and midbrain) infarct in the distribution of the small, penetrating cerebral arteries whose largest dimension is ≤1.5 cm on CT or ≤2.0 cm on MRI diffusion images/\<1.5 cm on T2 weighted MR images. The following are not considered lacunes: multiple simultaneous small deep infarcts, lateral medullary infarcts, and cerebellar infarcts. Patients with a clinical lacunar stroke syndrome and no infarct on imaging are excluded.
  * Absence of extracranial or intracranial atherosclerosis causing ≥50 percent luminal stenosis of the artery supplying the area of ischemia. Patients must undergo vascular imaging of the extracranial and intracranial vessels using either catheter angiography, CT angiogram (CTA), MR angiogram (MRA), or ultrasound, as considered appropriate by the treating physician and local principal investigator.
  * No major-risk cardioembolic source of embolism, including intracardiac thrombus, mechanical prosthetic cardiac valve, atrial myxoma or other cardiac tumors, moderate or severe mitral stenosis, myocardial infarction within the last 4 weeks, left ventricular ejection fraction \<30 percent, valvular vegetations, or infective endocarditis). Patent foramen ovale is not an exclusion. All patients must undergo electrocardiogram, transthoracic or transesophageal echocardiography (TTE or TEE) and at least 24 hours of cardiac rhythm monitoring (Holter monitor or telemetry or equivalent). Additional cardiac imaging, such as cardiac MRI, or cardiac CT will be performed at the discretion of the local treating physician and principal investigator. Additional cardiac rhythm monitoring, such as monitored cardiac outpatient telemetry (MCOT) or an implanted cardiac monitor, will be at the discretion of the treating physician and local principal investigator.
  * No other specific cause of stroke identified, such as arteritis, dissection, migraine, vasospasm, drug abuse, or hypercoagulability. Special testing, such as toxicological screens, serological testing for syphilis, and tests for hypercoagulability, will be performed at the discretion of the treating physician and local principal investigator.

Exclusion Criteria:

* History of atrial fibrillation (AF), AF on 12-lead ECG, or any AF of any duration during heart-rhythm monitoring prior to randomization.
* Clear indication for treatment-dose anticoagulant therapy, such as venous thromboembolism or a mechanical heart valve.
* Need for antiplatelet agent, such as aspirin or clopidogrel
* History of spontaneous intracranial hemorrhage.
* Chronic kidney disease with serum creatinine ≥2.5 mg/dL.For Canadian sites only, estimated creatinine clearance (eCrCl) \<15 mL/min is also an exclusion criterion.
* Active hepatitis or hepatic insufficiency with Child-Pugh score B or C.
* Clinically significant bleeding diathesis.
* Unresolved anemia (hemoglobin \<9 g/dL) or thrombocytopenia (\<100 x 10E9/L).
* Clinically significant gastrointestinal bleeding within the past year (e.g., not due to external hemorrhoids).
* At risk for pregnancy: premenopausal or postmenopausal woman within 12 months of last menses without a negative pregnancy test or not committing to adequate birth control, which includes an oral contraceptive, two methods of barrier birth control such as condom with or without spermicidal lubricant + diaphragm, or abstinence.
* Known allergy or intolerance to aspirin or apixaban.
* Concomitant participation in another clinical trial involving a drug or acute stroke intervention.
* Considered by the investigator to have a condition that precludes follow-up or safe participation in the trial.
* Inability of either participant or surrogate to provide written, informed consent for trial participation.

To be eligible for randomization, consented participants must meet criteria for atrial cardiopathy in addition to the inclusion/exclusion criteria above.

Atrial cardiopathy is defined as ≥1 of the following:

* PTFV1 \>5,000 μV\*ms on 12-lead ECG (ECG criterion).
* Serum NT-proBNP \>250 pg/mL (NT-proBNP criterion).
* Left atrial diameter index ≥3 cm/m2 on echocardiogram (i.e., severe left atrial enlargement) (ECHO criterion)

Primary outcomes:
measure: Number of Participants With Recurrent Stroke of Any Type
timeFrame: Up to 5 years of study participation.
Secondary outcomes:
measure: Number of Participants With Recurrent Ischemic Stroke or Systemic Embolism
timeFrame: Up to 5 years of study participation.
measure: Number of Participants With Recurrent Stroke of Any Type or Death From Any Cause
timeFrame: Up to 5 years of study participation.
measure: Number of Participants With Symptomatic Intracranial Hemorrhage (Including Symptomatic Hemorrhagic Transformation of an Ischemic Stroke)
timeFrame: Through 30 days after permanent discontinuation of the study drug, a duration of up to 5 years for each participant.
measure: Number of Participants With Major Hemorrhage Other Than Intracranial Hemorrhage.
timeFrame: Through 30 days after permanent discontinuation of the study drug, a duration of up to 5 years for each participant.
measure: Number of Participant Deaths From Any Cause Number of Participants With All-cause Mortality.
timeFrame: Through 30 days after permanent discontinuation of the study drug, a duration of up to 5 years for each participant.
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Mobile
country: United States
facility: University of South Alabama University Hospital
state: Alabama
city: Chandler
country: United States
facility: Chandler Regional Medical Center Chandler, AZ
state: Arizona
city: Phoenix
country: United States
facility: St. Joseph's Hospital and Medical Center
state: Arizona
city: Tucson
country: United States
facility: Banner University Medical Center - Tucson
state: Arizona
city: Carmichael
country: United States
facility: Mercy San Juan Medical Center (Dignity Health)
state: California
city: Castro Valley
country: United States
facility: Eden Medical Center
state: California
city: Downey
country: United States
facility: Rancho Los Amigos National Rehabilitation Center
state: California
city: Fountain Valley
country: United States
facility: Fountain Valley Regional Hospital and Medical Center
state: California
city: Fresno
country: United States
facility: Community Regional Medical Center
state: California
city: La Jolla
country: United States
facility: UCSD Health La Jolla
state: California
city: La Mesa
country: United States
facility: Sharp Grossmont Hospital
state: California
city: Long Beach
country: United States
facility: Long Beach Memorial Medical Center
state: California
city: Los Alamitos
country: United States
facility: Los Alamitos Medical Center
state: California
city: Los Angeles
country: United States
facility: Kaiser Permanente
state: California
city: Los Angeles
country: United States
facility: Keck Hospital Of USC
state: California
city: Los Angeles
country: United States
facility: Los Angeles County- USC Medical Center
state: California
city: Los Angeles
country: United States
facility: VA Greater Los Angeles - West LA VA Medical Center
state: California
city: Los Angeles
country: United States
facility: Ronald Reagan UCLA Medical Center
state: California
city: Orange
country: United States
facility: UC Irvine Medical Center
state: California
city: Sacramento
country: United States
facility: Sutter Medical Center
state: California
city: Salinas
country: United States
facility: Salinas Valley Memorial Hospital
state: California
city: San Diego
country: United States
facility: Scripps Mercy
state: California
city: San Diego
country: United States
facility: UCSD Medical Center - Hillcrest Hospital
state: California
city: San Diego
country: United States
facility: Kaiser Permanent San Diego Medical Center
state: California
city: San Diego
country: United States
facility: Sharp Memorial Hospital
state: California
city: San Francisco
country: United States
facility: San Francisco General
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center
state: California
city: San Jose
country: United States
facility: Good Samaritan
state: California
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: Englewood
country: United States
facility: Swedish Medical Center
state: Colorado
city: Grand Junction
country: United States
facility: St. Mary's Medical Center
state: Colorado
city: Bridgeport
country: United States
facility: St. Vincent's Medical Center
state: Connecticut
city: Hartford
country: United States
facility: Hartford Hospital
state: Connecticut
city: New Haven
country: United States
facility: Yale New Haven Hospital
state: Connecticut
city: Newark
country: United States
facility: Christiana Hospital
state: Delaware
city: Washington
country: United States
facility: Med-star Georgetown Univ.
state: District of Columbia
city: Washington
country: United States
facility: Medstar Washington
state: District of Columbia
city: Boca Raton
country: United States
facility: Boca Raton Regional Hospital
state: Florida
city: Gainesville
country: United States
facility: UF Health Shands
state: Florida
city: Jacksonville
country: United States
facility: Baptist Medical Center Jacksonville
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Miami
country: United States
facility: Jackson Memorial
state: Florida
city: Miami
country: United States
facility: Univ. Miami Hospital
state: Florida
city: Miami
country: United States
facility: Baptist Hospital of Miami
state: Florida
city: Sarasota
country: United States
facility: Intercoastal Medical Group - Hyde Park
state: Florida
city: Tampa
country: United States
facility: Tampa General
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Atlanta
country: United States
facility: Grady Memorial
state: Georgia
city: Honolulu
country: United States
facility: The Queen's Medical Center
state: Hawaii
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Chicago
country: United States
facility: Rush University
state: Illinois
city: Chicago
country: United States
facility: University of Illinois
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Peoria
country: United States
facility: OSF St. Francis Medical Center
state: Illinois
city: Springfield
country: United States
facility: Southern Illinois University Memorial Medical Center
state: Illinois
city: Springfield
country: United States
facility: St. John's Hospital (Prairie Research)
state: Illinois
city: Winfield
country: United States
facility: Central DuPage Hospital
state: Illinois
city: Des Moines
country: United States
facility: Multi-Specialty - Methodist Plaza/Unity Point
state: Iowa
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas
state: Kansas
city: Lexington
country: United States
facility: Baptist Health Lexington
state: Kentucky
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Louisville
country: United States
facility: University of Louisville Hospital
state: Kentucky
city: New Orleans
country: United States
facility: Ochsner Medical Center
state: Louisiana
city: Bangor
country: United States
facility: Eastern Maine Medical Center
state: Maine
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical
state: Massachusetts
city: Boston
country: United States
facility: Brigham & Womens Hospital
state: Massachusetts
city: Burlington
country: United States
facility: Lahey Hospital & Medical Center
state: Massachusetts
city: Worcester
country: United States
facility: U Mass Memorial Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan University Hospital
state: Michigan
city: Ann Arbor
country: United States
facility: VA Ann Arbor Healthcare System
state: Michigan
city: Detroit
country: United States
facility: Detroit Receiving Hospital
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Flint
country: United States
facility: McLaren Flint
state: Michigan
city: Grand Rapids
country: United States
facility: Mercy Health St. Mary's
state: Michigan
city: Grand Rapids
country: United States
facility: Spectrum Health
state: Michigan
city: Mount Clemens
country: United States
facility: McLaren Macomb, Mount Clemens, MI
state: Michigan
city: Petoskey
country: United States
facility: McLaren Northern Michigan
state: Michigan
city: Minneapolis
country: United States
facility: Abbott Northwestern Hospital
state: Minnesota
city: Minneapolis
country: United States
facility: Hennepin County
state: Minnesota
city: Minneapolis
country: United States
facility: Univ. of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Paul
country: United States
facility: Regions Hospital, St. Paul
state: Minnesota
city: Saint Paul
country: United States
facility: United Hospital
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Kansas City
country: United States
facility: Saint Luke's Hospital of Kansas City
state: Missouri
city: Saint Louis
country: United States
facility: St. Louis University Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Barnes Jewish Hospital
state: Missouri
city: Springfield
country: United States
facility: Cox Medical Center South
state: Missouri
city: Omaha
country: United States
facility: CHI Health Immanuel
state: Nebraska
city: Omaha
country: United States
facility: University of Nebraska
state: Nebraska
city: Camden
country: United States
facility: Cooper University Hospital,
state: New Jersey
city: New Brunswick
country: United States
facility: Robert Wood Johnson
state: New Jersey
city: Pennington
country: United States
facility: Capital Health Medical Center Hopewell
state: New Jersey
city: Albuquerque
country: United States
facility: Univ. New Mexico
state: New Mexico
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Brooklyn
country: United States
facility: Kings County Hospital
state: New York
city: Brooklyn
country: United States
facility: New York Presbyterian - Brooklyn Methodist Hospital
state: New York
city: Brooklyn
country: United States
facility: Maimonides Medical Center
state: New York
city: Brooklyn
country: United States
facility: NYU Langone Hospital - Brooklyn
state: New York
city: Brooklyn
country: United States
facility: Mount Sinai Beth Israel Brooklyn
state: New York
city: Buffalo
country: United States
facility: Buffalo General Medical Center
state: New York
city: Manhasset
country: United States
facility: North Shore University Hospital
state: New York
city: New York
country: United States
facility: NYU Langone
state: New York
city: New York
country: United States
facility: Mount Sinai West
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medicine
state: New York
city: New York
country: United States
facility: Lenox Hill Hospital
state: New York
city: Rochester
country: United States
facility: Strong Memorial Hospital
state: New York
city: Greensboro
country: United States
facility: Moses H. Cone Memorial Hospital
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Medical Center
state: North Carolina
city: Fargo
country: United States
facility: Sanford Medical Center Fargo
state: North Dakota
city: Akron
country: United States
facility: Akron General Medical Center
state: Ohio
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: Louis Stokes VA Medical Center
state: Ohio
city: Cleveland
country: United States
facility: UH Cleveland Medical Center
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: OSU Wexner
state: Ohio
city: Columbus
country: United States
facility: Ohio Health Riverside - Riverside Methodist Hospital
state: Ohio
city: Dayton
country: United States
facility: Miami Valley Hospita
state: Ohio
city: Toledo
country: United States
facility: Mercy St Vincent Medical Center
state: Ohio
city: Oklahoma City
country: United States
facility: OU Medical Center Oklahoma
state: Oklahoma
city: Portland
country: United States
facility: Legacy Emanuel
state: Oregon
city: Portland
country: United States
facility: Oregon Health and Sciences
state: Oregon
city: Allentown
country: United States
facility: Lehigh Valley Hospital
state: Pennsylvania
city: Altoona
country: United States
facility: UPMC Altoona
state: Pennsylvania
city: Lancaster
country: United States
facility: Lancaster General Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Presbyterian
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Columbia
country: United States
facility: Prisma Health Richland Hospital (formerly Palmetto Health)
state: South Carolina
city: Greenville
country: United States
facility: Prisma Health Greenville Memorial Hospital
state: South Carolina
city: Memphis
country: United States
facility: Methodist University Hospital
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Harlingen
country: United States
facility: Valley Bapist
state: Texas
city: Houston
country: United States
facility: Baylor College College of Medicine
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Houston
country: United States
facility: Memorial Hermann Texas Medical Center
state: Texas
city: San Antonio
country: United States
facility: Univ of Texas Health Science Center San Antonio
state: Texas
city: Temple
country: United States
facility: Scott & White Memorial Hospital - Temple
state: Texas
city: The Woodlands
country: United States
facility: Memorial Hermann The Woodlands Hospital
state: Texas
city: Murray
country: United States
facility: Intermountain Medical Center
state: Utah
city: Provo
country: United States
facility: Utah Valley Regional Medical Center
state: Utah
city: Salt Lake City
country: United States
facility: Univ of Utah
state: Utah
city: Salt Lake City
country: United States
facility: George E Whalen VA
state: Utah
city: Charlottesville
country: United States
facility: UVA Medical Center
state: Virginia
city: Richmond
country: United States
facility: Bon Secours St. Mary's Hospital
state: Virginia
city: Olympia
country: United States
facility: Providence St. Peter Hospital
state: Washington
city: Seattle
country: United States
facility: Harborview Medical Center
state: Washington
city: Seattle
country: United States
facility: Puget Sound VA
state: Washington
city: Seattle
country: United States
facility: Swedish Medical Center - Cherry Hill Campus
state: Washington
city: Morgantown
country: United States
facility: WVU Healthcare Ruby Memorial
state: West Virginia
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Milwaukee
country: United States
facility: Froedtert Hospital
state: Wisconsin
city: Calgary
country: Canada
facility: University of Calgary - Foothills Medical Centre
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Lethbridge
country: Canada
facility: Neurologic Research Center
state: Alberta
city: Kelowna
country: Canada
facility: Kelowna General Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Brandon
country: Canada
facility: Brandon Regional Health Center
state: Manitoba
city: Hamilton
country: Canada
facility: Hamilton General Hospital
state: Ontario
city: Kingston
country: Canada
facility: Kingston General Hospital
state: Ontario
city: London
country: Canada
facility: London Health Sciences Center
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Center
state: Ontario
city: Québec
country: Canada
facility: Enfant-Jesus Hospital
state: Quebec
city: Saskatoon
country: Canada
facility: Royal University Hospital
state: Saskatchewan
Study officials:
affiliation: Columbia University
name: Randolph S Marshall, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kamel H, Okin PM, Elkind MS, Iadecola C. Atrial Fibrillation and Mechanisms of Stroke: Time for a New Model. Stroke. 2016 Mar;47(3):895-900. doi: 10.1161/STROKEAHA.115.012004. Epub 2016 Jan 19. No abstract available.
citation: Yaghi S, Kamel H, Elkind MS. Potential new uses of non-vitamin K antagonist oral anticoagulants to treat and prevent stroke. Neurology. 2015 Sep 22;85(12):1078-84. doi: 10.1212/WNL.0000000000001817. Epub 2015 Jul 17.
citation: Kamel H, Okin PM, Longstreth WT Jr, Elkind MS, Soliman EZ. Atrial cardiopathy: a broadened concept of left atrial thromboembolism beyond atrial fibrillation. Future Cardiol. 2015 May;11(3):323-31. doi: 10.2217/fca.15.22.
citation: Yaghi S, Moon YP, Mora-McLaughlin C, Willey JZ, Cheung K, Di Tullio MR, Homma S, Kamel H, Sacco RL, Elkind MS. Left atrial enlargement and stroke recurrence: the Northern Manhattan Stroke Study. Stroke. 2015 Jun;46(6):1488-93. doi: 10.1161/STROKEAHA.115.008711. Epub 2015 Apr 23.
citation: Longstreth WT Jr, Kronmal RA, Thompson JL, Christenson RH, Levine SR, Gross R, Brey RL, Buchsbaum R, Elkind MS, Tirschwell DL, Seliger SL, Mohr JP, deFilippi CR. Amino terminal pro-B-type natriuretic peptide, secondary stroke prevention, and choice of antithrombotic therapy. Stroke. 2013 Mar;44(3):714-9. doi: 10.1161/STROKEAHA.112.675942. Epub 2013 Jan 22.