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

Summary

Background

The primary outcome results for the SPS3 trial suggested that a lower systolic target blood pressure (<130 mm Hg) might be beneficial for reducing the risk of recurrent stroke compared with a higher target (130–149 mm Hg), but that the addition of clopidogrel to aspirin was not beneficial compared with aspirin plus placebo. In this prespecified secondary outcome analysis of the SPS3 trial, we aimed to assess whether blood pressure reduction and dual antiplatelet treatment affect changes in cognitive function over time in patients with cerebral small vessel disease.

Methods

In the SPS3 trial, patients with recent (within 6 months) symptomatic lacunar infarcts from 81 centres in North America, Latin America, and Spain were randomly assigned, in a two-by-two factorial design, to target levels of systolic blood pressure (1:1; 130–149 mm Hg vs <130 mm Hg; open-label) and to a once-daily antiplatelet treatment (1:1; aspirin 325 mg plus clopidogrel 75 mg vs aspirin 325 mg plus placebo; double-blind). For this analysis, the main cognitive outcome was change in Cognitive Abilities Screening Instrument (CASI) during follow-up. Patients were tested annually for up to 5 years, during which time the mean difference in systolic blood pressure was 11 mm Hg (SD 16) between the two targets (138 mm Hg vs 127 mm Hg at 1 year). We used linear mixed models to compare changes in CASI Z scores over time. The SPS3 trial is registered with ClinicalTrials.gov, number NCT00059306.

Findings

The study took place between March 23, 2003, and April 30, 2012. 2916 of 3020 SPS3 participants (mean age 63 years [SD 11]) with CASI scores at study entry were included in the analysis, with a median follow-up of 3·0 years (IQR 1·0–4·9). Mean changes in CASI Z scores from study entry to assessment at years 1 (n=2472), 2 (n=1968), 3 (n=1521), 4 (n=1135), and 5 (n=803) were 0·12 (SD 0·83), 0·15 (0·84), 0·16 (0·95), 0·19 (0·99), and 0·14 (1·09), respectively. Changes in CASI Z scores over time did not differ between assigned antiplatelet groups (p=0·858) or between assigned blood pressure target groups (p=0·520). There was no interaction between assigned antiplatelet groups and assigned blood pressure target groups and change over time (p=0·196).

Interpretation

Cognitive function is not affected by short-term dual antiplatelet treatment or blood pressure reduction in fairly young patients with recent lacunar stroke. Future studies of cognitive function after stroke should be of longer duration or focus on patients with higher rates of cognitive decline.

Funding

US National Institute of Neurological Disorders and Stroke.

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.