SPS3 2013

Methods	Multicentre open‐label clinical trial, ITT strategy, 2 x 2 factorial design with randomization to both an antiplatelet intervention and a target level of SBD control. The follow‐up was 0 to 8.6 years (mean 3.7 years)
Participants	Eligible participants were aged ≥ 30 years, were normotensive or hypertensive, had a recent (within 180 days), symptomatic, MRI‐confirmed lacunar stroke, and were without surgically amenable ipsilateral carotid artery stenosis or high‐risk cardio‐embolic sources. Main exclusion criteria included disabling stroke (modified Rankin score ≥ 4), previous intracranial haemorrhage from non traumatic causes, or cortical ischaemic stroke. Baseline characteristics for participants included in the review (% or mean ± SD): men/women (63/37%); age (63 years); SBP (143 ± 19 mmHg); DBP (79 ± 11 mmHg); diabetes (37%); current smoker (20%); ethnic group: White (51%), non White (49%). Types of drugs at 1 year: thiazides (45%), ACEI/ARB (63%), CCB (32%), BB (25%), other (12%). Previous cardiovascular condition: IHD (10%), stroke (99%). Countries: USA, Canada, Mexico, Ecuador, Peru, Chile, Argentina and Spain
Interventions	Standard (higher) target: SBP 130 to 149 mmHg Lower target: SBP < 130 mmHg
Outcomes	The primary outcome was time to recurrent stroke (first of fatal or non fatal ischaemic stroke or central nervous system haemorrhage). All possible clinical stroke events are assessed at the clinical site by both the local neurology investigator and a neurologist blinded to the assigned treatment arms. Secondary outcomes included acute MI and death, classified as vascular or non vascular. Safety events were major cognitive decline, major extracranial (systemic) haemorrhage, serious complication of hypotension and other SPS3‐related serious adverse events. Serious adverse events were major vascular events and severe adverse events related to hypotension. No information about non vascular deaths or severe adverse events other than hypotension‐related was provided
Funding sources	National Institute of Neurological Disorders and Stroke (USA)
Declarations of interest	The authors declared no conflicts of interest
Notes	The antiplatelet component of the trial was terminated at the recommendation of the data and safety monitoring committee because of lack of efficacy combined with evidence of harm. The blood pressures achieved at the end of the trial were: standard target: SBP 138 ± 1 mmHg; lower target: SBP 127 ± 1 mmHg
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randomisation assignments were generated using a permuted‐block design (variable block size), stored in each clinical centre’s electronic data entry system, and protected from preview" (pp. 164‐75)
Allocation concealment (selection bias)	Low risk	"Randomisation assignments were generated using a permuted‐block design (variable block size), stored in each clinical centre’s electronic data entry system, and protected from preview" (pp. 164‐75)
Blinding of participants and personnel (performance bias) All outcomes	High risk	The study design was not compatible with blinding of participants and personnel
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"The Prospective, Randomized, Open‐label, Blinded Endpoint (PROBE) study design, a standard for international blood pressure trials, was utilised" (pp. 164‐75)
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	90 (3%) participants were lost to follow‐up and an additional 465 (15%) ended follow‐up early for the following reasons: withdrawn consent (N = 242), site closure (N = 151), physician request (N = 12), and other reasons (N = 60). No information about how these numbers refer to higher‐target and lower‐target groups
Selective reporting (reporting bias)	High risk	Only serious adverse events related to hypotension and blood pressure management were reported. Despite repeated attempts to obtain clarification from the study authors, no response was received
Other bias	Low risk	All SPS3 participants met the base cardiovascular disease criteria

Abbreviations: ACEI ‐ angiotensin converting enzyme inhibitors; ARB ‐ angiotensin II receptor blocker; BB ‐ beta blocker; CCB ‐ calcium channel blocker; CHF ‐ congestive heart failure; CKD ‐ chronic kidney disease; CVD ‐ cardiovascular disease; DBP ‐ diastolic blood pressure; ECG ‐ electrocardiography/electrocardiogram; GFR ‐ glomerular filtration rate; IHD ‐ ischaemic heart disease; ITT ‐ intention‐to‐treat; LVH ‐ left ventricular hypertrophy; MBP ‐ mean blood pressure; MI ‐ myocardial infarction; PVD ‐ peripheral vascular disease; RCT ‐ randomized controlled trial; SBP ‐ systolic blood pressure; SD ‐ standard deviation; TIA ‐ transient ischaemic attack.