Antithrombotic therapy to prevent cognitive decline in people with small vessel disease on neuroimaging but without dementia


Disruption of blood flow to the brain can cause problems with memory and thinking. In the condition called 'cerebral small vessel disease', there is damage to the smallest blood vessels that run deep in the brain. This damage can cause stroke but can also be seen on brain scans in people with no obvious stroke symptoms. Cerebral small vessel disease usually gets worse over time, and in some people can cause a decline in memory and thinking. If this decline gets severe enough to affect a person's ability to manage their daily activities independently, then it is described as a type of vascular dementia. We know that blood-thinning medications such as aspirin can prevent stroke. We wanted to know whether blood-thinning medications might also prevent the decline in memory and thinking that is seen in cerebral small vessel disease.

Review question 

Are blood-thinning medications effective and safe in preventing the decline in memory and thinking in people with cerebral small vessel disease?

What we did 

We searched the medical literature up to 21 July 2021 looking for studies that compared blood-thinning medications given over at least 24 weeks to a comparator, which could have been either usual care or a placebo (dummy) tablet. To make the comparison fair, the studies had to assign people randomly to blood-thinning medications or the comparator treatment. We were interested in the effects on participants' performance in memory and thinking tests, their ability to look after themselves, their risk of developing dementia and stroke, and side effects (especially from bleeding). Because the studies were so different from each other in terms of the type of participants, medications and assessments, we were unable to combine the results in analyses. Rather, we described the results of individual studies and assessed how confident we were in their findings.

What we found 

We included three studies with 3384 participants. These studies were very different in terms of the participants (some with and some without stroke), the medications studied (single and combinations of different blood-thinners), and how the effects on memory and thinking were measured (different tests used for assessment). No trial consistently demonstrated an improvement in performance in memory and thinking tests or in daily activities. No trial assessed for a new diagnosis of dementia. There was suggestion of blood-thinning medications possibly causing an increased risk of bleeding, including gastrointestinal bleeding, but the numbers were too small to be certain that this was not just a chance difference. Overall, we considered that the quality of the evidence was poor for answering our review question regarding memory and thinking. Much of the information we needed was not reported. Two of the three studies were small, meaning that there was uncertainty around their results. In the only study that reported any benefit from blood-thinning medication, different measures of memory and thinking did not all agree with each other. Lastly, where there was an improvement in memory and thinking, the size of this improvement may have been too small to make a noticeable difference to the individual in reality.


We found no convincing evidence that taking blood-thinning medications is beneficial for memory and thinking in people with cerebral small vessel disease. However, the studies were very different from each other, and each one had limitations with regard to our review question.

Authors' conclusions: 

We found no convincing evidence to suggest any clinically relevant cognitive benefit of using antithrombotic therapy in addition to standard treatment in people with cerebral small vessel disease but without dementia, but there may be an increased bleeding risk with this approach. There was marked heterogeneity across the trials and the certainty of the evidence was generally poor.

Read the full abstract...

Cerebral small vessel disease is a progressive disease of the brain's deep perforating blood vessels. It is usually diagnosed based on lesions seen on brain imaging. Cerebral small vessel disease is a common cause of stroke but can also cause a progressive cognitive decline. As antithrombotic therapy is an established treatment for stroke prevention, we sought to determine whether antithrombotic therapy might also be effective in preventing cognitive decline in people with small vessel disease.


To assess the effects of antithrombotic therapy for prevention of cognitive decline in people with small vessel disease on neuroimaging but without dementia.

Search strategy: 

We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Review Group's Specialised Register, and the Cochrane Stroke Group's Specialised Register; the most recent search was on 21 July 2021. We also searched MEDLINE, Embase, four other databases and two trials registries. We searched the reference lists of the articles retrieved from these searches. As trials with a stroke focus may include relevant subgroup data, we complemented these searches with a focussed search of all antithrombotic titles in the Cochrane Stroke Group database. 

Selection criteria: 

We included randomised controlled trials (RCT) of people with neuroimaging evidence of at least mild cerebral small vessel disease (defined here as white matter hyperintensities, lacunes of presumed vascular origin and subcortical infarcts) but with no evidence of dementia. The trials had to compare antithrombotic therapy of minimum 24 weeks' duration to no antithrombotic therapy (either placebo or treatment as usual), or compare different antithrombotic treatment regimens. Antithrombotic therapy could include antiplatelet agents (as monotherapy or combination therapy), anticoagulants or a combination.

Data collection and analysis: 

Two review authors independently screened all the titles identified by the searches. We assessed full texts for eligibility for inclusion according to our prespecified selection criteria, extracted data to a proforma and assessed risk of bias using the Cochrane tool for RCTs. We evaluated the certainty of evidence using GRADE. Due to heterogeneity across included participants, interventions and outcomes of eligible trials, it was not possible to perform meta-analyses.

Main results: 

We included three RCTs (3384 participants). One study investigated the effect of antithrombotic therapy in participants not yet on antithrombotic therapy; two studies investigated the effect of additional antithrombotic therapy, one in a population already taking a single antithrombotic agent and one in a mixed population (participants on an antithrombotic drug and antithrombotic-naive participants). Intervention and follow-up durations varied from 24 weeks to four years.

Jia 2016 was a placebo-controlled trial assessing 24 weeks of treatment with DL-3-n-butylphthalide (a compound with multimodal actions, including a putative antiplatelet effect) in 280 Chinese participants with vascular cognitive impairment caused by subcortical ischaemic small vessel disease, but without dementia. There was very low-certainty evidence for a small difference in cognitive test scores favouring treatment with DL-3-n-butylphthalide, as measured by the 12-item Alzheimer’s Disease Assessment Scale-Cognitive subscale (adjusted mean difference −1.07, 95% confidence interval (CI) −2.02 to −0.12), but this difference may not be clinically relevant. There was also very low-certainty evidence for greater proportional improvement measured with the Clinician Interview-Based Impression of Change-Plus Caregiver Input (57% with DL-3-n-butylphthalide versus 42% with placebo; P = 0.01), but there was no difference in other measures of cognition (Mini-Mental State Examination and Clinical Dementia Rating) or function. There was no evidence of a difference in adverse events between treatment groups.

The SILENCE RCT compared antithrombotic therapy (aspirin) and placebo during four years of treatment in 83 participants with 'silent brain infarcts' who were on no prior antithrombotic therapy. There was very low-certainty evidence for no difference between groups across various measures of cognition and function, rates of stroke or adverse events.

The Secondary Prevention of Subcortical Stroke Study (SPS3) compared dual antiplatelet therapy (clopidogrel plus aspirin) to aspirin alone in 3020 participants with recent lacunar stroke. There was low-certainty evidence of no effect on cognitive outcomes as measured by the Cognitive Abilities Screening Instruments (CASI) assessed annually over five years. There was also low-certainty evidence of no difference in the annual incidence of mild cognitive decline between the two treatment groups (9.7% with dual antiplatelet therapy versus 9.9% with aspirin), or the annual stroke recurrence rate (2.5% with dual antiplatelet therapy versus 2.7% with aspirin). Bleeding risk may be higher with dual antiplatelet therapy (hazard ratio (HR) 2.15, 95% CI 1.49 to 3.11; low certainty evidence), but there may be no significant increase in intracerebral bleeding risk (HR 1.52, 95% CI 0.79 to 2.93; low-certainty evidence).

None of the included trials assessed the incidence of new dementia.