Pearce SPS3 2014.

Study characteristics
Methods	Design: randomised, double‐blind, placebo‐controlled trial Location/setting: 81 clinical centres in North America, Latin America and Spain (7 countries) Date of study: March 2003 to May 2012 (enrolment period 2003–2011) Sample size: 3020 people, but only 2916 participants had cognitive assessment (CASI) assessment at study entry. Randomisation: among the 2916 participants with CASI assessment at study entry, 1468 were assigned to aspirin + clopidogrel and 1448 to aspirin + placebo; 74% of the 2916 participants had the CASI assessment completed at their last annual visit. Quote: "Participants were simultaneously randomised in a 2‐by‐2 factorial design to both an antiplatelet intervention (1:1. double‐blind, aspirin + placebo vs. aspirin + clopidogrel). Randomization assignments (permuted block design of variable size, stratified by clinical centre and hypertension status) were unavailable for preview and stored electronically at each clinical centre and at the SPS3 Statistical Centre."
Participants	Number in study: 2916 Mean age: aspirin + clopidogrel: 63.5 (SD 10.8) years; aspirin + placebo: 63.1 (SD 10.7) years Female: aspirin + clopidogrel: 557 (38%); aspirin + placebo: 531 (37%) Education: aspirin + clopidogrel: 0–8 years: 391 (27%); 9–12 years: 527 (36%); > 12 years: 550 (37%); aspirin + placebo: 0–8 years: 374 (26%); 9–12 years: 578 (40%); > 12 years: 496 (34%) Ethnicity: aspirin + clopidogrel: White, not Hispanic: 751 (51%); Hispanic: 454 (31%); Black: 237 (16%); other or multiracial: 26 (2%); aspirin + placebo: White, not Hispanic: 745 (51%); Hispanic: 452 (31%); Black: 236 (16%); other or multiracial: 15 (1%) Medical history: aspirin + clopidogrel: diabetes: 524 (36%); hypertension: 1107 (75%); ischaemic heart disease: 157 (11%); lacunar stroke: 154 (11%); subcortical TIA: 80 (5%); aspirin + placebo: diabetes: 546 (38%); hypertension: 1172 (74%); ischaemic heart disease: 150 (10%); lacunar stroke: 146 (10%); subcortical TIA: 78 (5%) Days from index event to neuropsychological testing, mean: aspirin + clopidogrel: 78 (SD 50) days; aspirin + placebo: 74 (SD 51) days Modified Rankin stroke disability score: aspirin + clopidogrel: 0: 230 (16%); 1: 763 (52%); 2: 348 (24%); 3: 127 (9%); aspirin + placebo: 0: 209 (14%); 1: 741 (51%); 2: 368 (25%); 3: 130 (9%) Barthel index score ≥ 95: aspirin + clopidogrel: 1173 (80%); aspirin + placebo: 1148 (79%) Mild cognitive impairment: aspirin + clopidogrel: 649 (45%); aspirin + placebo: 654 (46%) Additional small subcortical infracts on MRI: aspirin + clopidogrel: 573 (40%); aspirin + placebo: 553 (39%) White matter lesion (ARWMC score): aspirin + clopidogrel: none/mild (score 0–4): 709 (49%); moderate (score 5–8): 407 (28%); severe (score ≥ 9): 327 (23%); aspirin + placebo: none/mild (score 0–4): 728 (51%); moderate (score 5–8): 397 (28%); severe (≥ 9): 298 (21%) Inclusion criteria People with symptomatic small subcortical stroke (S3) confirmed by MRI, randomised within 6 months of S3 qualification and satisfying all the following criteria Clinical lacunar stroke syndrome (modified from the Fisher 1991 criteria) Absence of signs and symptoms of cortical dysfunction No ipsilateral cervical carotid stenosis (≥ 50%), if the qualifying event was hemispheric No major‐risk cardioembolic source requiring anticoagulation or other specific therapy (minor‐risk cardioembolic sources were allowed if anticoagulation was not prescribed) MRI presence of an S3 (≤ 2 cm in diameter) corresponding to the qualifying event (required for all brainstem events) or multiple S3s and absence of cortical stroke and large subcortical stroke (recent or remote) Exclusion criteria Disabling stroke (modified Rankin scale ≥ 4) Previous intracranial haemorrhage (excluding traumatic) or haemorrhagic stroke Aged < 30 years High risk of bleeding (e.g. recurrent gastrointestinal or genitourinary bleeding, active peptic ulcer disease) Anticipated requirement for long‐term use of anticoagulants (e.g. recurrent deep vein thrombosis) or other antiplatelets Prior cortical or retinal stroke/TIA (diagnosed either clinically or by neuroimaging) Prior ipsilateral carotid endarterectomy/stent Impaired renal function: glomerular filtration rate < 40 mL/minute/1.73 m2  Intolerance or contraindications to aspirin or clopidogrel (including thrombocytopenia, prolonged INR) MMSE < 24 (adjusted for age and education) (Crum 1993) Medical contraindication to MRI Pregnancy or women of child‐bearing potential who were not following an effective method of contraception Unable or unwilling to provide informed consent Unlikely to be compliant with therapy/unwilling to return for frequent clinic visits People 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 Consent: (quote): "Participation required written informed consent and study protocol approval by the human research subjects committee at each study centre." Protection of human participants: (quote): "All clinical sites are required to comply with their local Institutional Review Boards and Human Subject Protection policies. All participants provide written informed consent in their preferred language (English, French, or Spanish) before undergoing any study procedures. The safety of all participants is closely monitored."
Interventions	Both groups received antiplatelet intervention. Pharmacological intervention (dual antiplatelet therapy): aspirin + clopidogrel Control (single antiplatelet therapy): aspirin + placebo Treatment duration: 3 years
Outcomes	Mean follow‐up: 3.4 years Primary cognitive outcome Change in CASI during follow‐up SPS3 primary outcome Time to recurrent stoke (first of fatal or non‐fatal ischaemic stroke or central nervous system haemorrhage) SPS3 secondary outcomes Rate of cognitive decline measured by CASI Incident mild cognitive impairment, defined as: no cognitive impairment if no definite impairment was present in any cognitive domain; mild cognitive impairment (single amnestic type) if there was definite impairment on ≥ 2 of the memory (California Verbal Learning Test) scores, with non‐memory scores normal; mild cognitive impairment (multidomain) if there was definite impairment on ≥ 2 memory test scores, and definite impairment on ≥ 2 non‐memory test scores (block design, symbol search, Controlled Oral Word Association, and digit span, or definite impairment on the Clox test if the participant had > 8 years of education); and mild cognitive impairment (non‐amnestic) if there was definite impairment on ≥ 2 non‐memory test scores only. Definite impairment was defined as a Z score ≤ –1.5, ≥ 1.5 SDs below the mean. TIA, defined as an acute focal neurological deficit due to cerebral ischaemia that resolved completely within 24 hours, regardless of neuroimaging findings Acute myocardial infarct, defined by standard criteria consisting of ECG and cardiac enzyme changes requiring acute hospitalisation Non‐central nervous system thromboembolism, and Death, classified as vascular or non‐vascular
Notes	PubMed link: www.ncbi.nlm.nih.gov/pubmed/25453457 ClinicalTrials.gov Registry number: NCT00059306 Funding source: National Institute of Neurological Disorders and Stroke (US) (U01 NS38529‐04A1) Role of funding source: (quote) "The sponsor of the study participated in study design, data collection, data analysis and data interpretation." Declaration of interest: (quote) "The authors declare that they have no conflicts of interest."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Participants were simultaneously randomised in a 2‐by‐2 factorial design to both an antiplatelet intervention (1:1, double‐blind, aspirin + placebo vs. aspirin + clopidogrel)."
Allocation concealment (selection bias)	Low risk	Quote: "Randomization assignments (permuted block design of variable size, stratified by clinical centre and hypertension status) were unavailable for preview and stored electronically at each clinical centre and at the SPS3 Statistical Centre."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "All SPS3 participants take enteric‐coated aspirin 325mg daily and are randomly assigned (double‐blind) to take clopidogrel 75mg daily or the matching placebo. Antiplatelet medications are provided to patients at randomisation and each quarterly follow‐up visit, with adherence measured by pill counts."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "All possible outcome and safety events are reviewed by the blinded Events Adjudication Committee made up of neurologists, cardiologists, and internists who are not otherwise involved in SPS3. Event materials, including diagnostic information, blinded to patient identity are submitted by the clinical sites to the Events Coordinator, who blinds them to any information potentially revealing SPS3 treatment assignments and distributes to at least two committee members for review."
Incomplete outcome data (attrition bias) All outcomes	High risk	74% of the 2916 participants had the CASI assessment completed at their last annual visit. Missing cognitive assessments likely to be related to cognitive outcome.
Selective reporting (reporting bias)	Low risk	Comment: both primary and secondary outcomes were reported as described in the study protocol.
Other bias	Low risk	No evidence of other bias noted.

ADL: activities of daily living; ARWMC: age‐related white matter change; CASI: Cognitive Abilities Screening Instrument; CDR: Clinical Dementia Rating; CDR‐SB: Clinical Dementia Rating scale Sum of Boxes; CIBIC‐plus: Clinician Interview‐Based Impression of Change‐Plus Caregiver Input; DSM‐IV: Diagnostic and Statistical Manual of Mental Disorders Fourth Edition; ECG: electrocardiogram; HAMD: Hamilton Depression Scale; INR: international normalised ratio; IQR: interquartile range; MMSE: Mini‐Mental State Examination; MRI: magnetic resonance imaging; NPI: Neuropsychiatric Inventory; NYHA: New York Heart Association; SBI: silent brain infarction; SD: standard deviation; SPS3: Secondary Prevention of Small Subcortical Strokes; TIA: transient ischaemic attack; WML: white matter lesions.