ArticlesEffects 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
Introduction
Hypertension and stroke are well established risk factors for cognitive impairment and vascular dementia.1, 2, 3, 4, 5 Lacunar strokes are a common cause of cognitive impairment.1, 6 Lowering blood pressure reduces stroke;7, 8, 9 therefore, effective control of blood pressure in patients who have had a lacunar stroke might result in reduction of cognitive impairment. Results of clinical trials that have tested blood pressure lowering to reduce dementia or cognitive decline in patients who have had a stroke10, 11 and in those without cerebrovascular disease12, 13, 14 have been conflicting. Similarly, no convincing data exist to support the use of antithrombotic treatments in the prevention of cognitive decline.15, 16
The Secondary Prevention of Small Subcortical Strokes (SPS3) trial assessed two interventions for prevention of recurrent stroke in patients with lacunar strokes: dual versus single drug antiplatelet treatment, and lower (<130 mm Hg) versus higher (130–149 mm Hg) systolic blood pressure targets. Risk of recurrent stroke was not reduced with the addition of clopidogrel to aspirin, and the antiplatelet part of the trial was stopped 8 months before the scheduled end date because of increased mortality in the dual antiplatelet treatment group; the lower blood pressure target was associated with a non-significant (p=0·08) reduction in stroke recurrence of 19% and reduced intracerebral haemorrhage by 63% (p=0·03) compared with the higher target, with no safety concerns.8, 17 Here we report the effect of each of these interventions on the prespecified secondary endpoint of change in cognitive function over time as measured by the Cognitive Abilities Screening Instrument (CASI)18 during a follow-up of up to 5 years.
Section snippets
Study design
Study rationale, design, participant characteristics, and the primary outcomes results of SPS3 have been previously reported.8, 17, 18, 19, 20 In brief, SPS3 was a randomised clinical trial done in 81 clinical centres in North America, Latin America, and Spain. Eligible participants had a recent (within 6 months) lacunar stroke documented on MRI and were without major-risk cardioembolic source, ipsilateral carotid stenosis of 50% or higher (in hemispheric infarct cases), or evidence of previous
Results
The study took place between March 23, 2003, and April 30, 2012 (enrolment period 2003–11). Of the 3020 participants in SPS3, 2916 had the CASI assessment at study entry; we were unable to do standardised testing for 104 participants for several reasons (tests not available in a participant's native language, participant refusal, and unavailability of a certified examiner). The 104 participants without testing were similar in vascular risk profile to those with testing (data not shown), except
Discussion
The results of the SPS3 study, which included a well characterised population of patients with recent lacunar stroke and detailed cognitive assessments, provide the most reliable evidence of the effects of dual antiplatelet treatment (aspirin plus clopidogrel) versus single antiplatelet therapy with (aspirin plus placebo) and lower (<130 mm Hg systolic) versus higher (130–149 mm Hg systolic) blood pressure targets on cognitive function in patients with cerebral small vessel disease. Although
References (36)
- et al.
Poststroke dementia
Lancet Neurol
(2005) - et al.
Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis
Lancet Neurol
(2009) - et al.
15-year longitudinal study of blood pressure and dementia
Lancet
(1996) - et al.
Effects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial: a double-blind, active and placebo-controlled study
Lancet Neurol
(2008) - et al.
Renin-angiotensin system blockade and cognitive function in patients at high risk of cardiovascular disease: analysis of data from the ONTARGET and TRANSCEND studies
Lancet Neurol
(2011) - et al.
Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial
Lancet
(1998) - et al.
Incident dementia and blood pressure lowering in the Hypertension in the Very Elderly Trial cognitive function assessment (HYVET-COG): a double-blind, placebo controlled trial
Lancet Neurol
(2008) - et al.
Clinical features and racial/ethnic differences among the 3020 participants in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial
J Stroke Cerebrovasc Dis
(2013) - et al.
Normative data stratified by age and education for two measures of verbal fluency: FAS and animal naming
Arch Clin Neuropsychol
(1999) - et al.
Effect of baseline cognitive function and antihypertensive treatment on cognitive and cardiovascular outcomes: Study on COgnition and Prognosis in the Elderly (SCOPE)
Am J Hypertens
(2005)
“Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician
J Psychiatr Res
Cognitive impairment in lacunar strokes: the SPS3 trial
Ann Neurol
Update on hypertension and Alzheimer's disease
Neurol Res
Cognitive impairment after lacunar stroke: systematic review and meta-analysis of incidence, prevalence and comparison with other stroke subtypes
J Neurol Neurosurg Psychiatry
Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack
Lancet
Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial
Lancet
Effect of antihypertensive treatment in patients having already suffered from stroke. Gathering the evidence
Stroke
Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease
Arch Intern Med
Cited by (106)
Cerebral small vessel disease alters neurovascular unit regulation of microcirculation integrity involved in vascular cognitive impairment
2022, Neurobiology of DiseaseCitation Excerpt :However, in CADASIL patients older than 80 years, brain perfusion might depend on elevated blood pressure, and rapid or large blood pressure reductions could lead to hypoperfusion and rapid acceleration of CSVD pathology (Pettersen et al., 2017). In the Secondary Prevention of Small Subcortical Stroke (SPS3) trial among 3020 patients with lacunar ischemic stroke (mean age 63 years, follow-up 3 years), the target systolic blood pressure < 130 mmHg did not reduce recurrent stroke or cognitive decline but significantly reduced the rate of hemorrhagic stroke (Pearce et al., 2014). Similarly, another study showed that lowering blood pressure using perindopril in CAA patients decreased intracerebral hemorrhage (ICH) by 77% over a mean of 3.9 years of follow-up (Arima et al., 2010).
Ticagrelor for prevention of stroke and cognitive impairment in patients with vascular high-risk factors: A meta-analysis of randomized controlled trials
2022, International Journal of CardiologyEuropean stroke organisation (ESO) guideline on cerebral small vessel disease, part 2, lacunar ischaemic stroke
2024, European Stroke Journal