In this international multicentre study, the presence of asymptomatic embolisation, detected by TCD, predicted subsequent ipsilateral stroke and TIA and also ipsilateral stroke alone. This suggests that TCD might be useful to identify patients with asymptomatic carotid stenosis who are at increased risk of stroke or TIA, and also to identify patients at low risk in whom surgical intervention will not be beneficial. The technique enabled identification of a group of patients who did not have embolic signals in whom the annual risk of stroke was less than 1%; at this level of risk carotid endarterectomy is not associated with benefit and might actually incur risk.6
Previous studies in symptomatic carotid stenosis have shown that embolic signals predict future stroke risk.12,13
However, data from asymptomatic carotid stenosis, in which there is a greater potential clinical application, have been less conclusive.13,15,16
One study in 319 patients, of whom 210 were available for analysis at 2 years, reported a significant association between embolic signals at baseline and future risk of stroke and TIA.15
In this single-centre study, analysis of embolic signals was done online, rather than by subsequent masked analysis as in ACES; however, the proportion of individuals with embolic signals was similar to that in ACES (10% on a single baseline recording). A second study in 202 individuals with subsequent offline analysis of embolic signals found no association between embolic signals at baseline and subsequent stroke risk.16
Repeat recordings were done in some individuals at 6-monthly intervals and there seemed to be fewer events in patients who consistently did not have embolic signals. The hazard ratio for stroke associated with the presence of embolic signals in ACES was midway between these two studies. Meta-analysis of the results of the primary analysis from ACES with all previous studies showed a significant association between embolic signals and subsequent stroke risk. Meta-analysis also showed a significant association between embolic signals and the combined endpoint of stroke and TIA, although there was heterogeneity between studies for this analysis.
Optimal management of asymptomatic carotid stenosis remains controversial, and practices vary between different clinicians and in different countries. Data from large randomised trials have shown a significant effect of endarterectomy in preventing future stroke, but with a small absolute benefit.3,4
have reported that, with improved medical treatment, the annual risk of stroke in patients with asymptomatic carotid stenosis is lower than that reported in the carotid endarterectomy trials (nearer to 1% in these trials compared with 2·3% in ACAS),3
which further reduces the benefit of surgical intervention. This is consistent with the annual risk of ipsilateral stroke of 1·2% (ten ipsilateral strokes over 2 years) reported in ACES. This improvement in natural history with better medical therapy might make surgical intervention hazardous.6
Carotid stenting has been suggested as an alternative to endarterectomy, but as yet there are no data showing it is safer than endarterectomy for asymptomatic carotid stenosis.
Despite the small absolute benefit from intervention, asymptomatic carotid stenosis accounts for a substantial stroke burden. Most patients with carotid stenosis will not have TIA or minor stroke before disabling stroke. Therefore, an appealing approach is to identify the small group of patients with asymptomatic carotid stenosis and high risk of stroke who would benefit most from surgical intervention. Several markers of high risk have been suggested, including clinical risk factors, degree of carotid stenosis, and plaque characteristics on imaging. However, none have been consistently supported by data from prospective studies.2
The ACES results show that TCD embolic signal detection can be used to identify a high-risk group.
We chose our primary endpoint to allow sufficient numbers of endpoints to detect an association within our sample size. However, we were able to also detect an association with the more robust endpoint of stroke alone. This association was stronger, perhaps because diagnosis of stroke is more reliable than that of TIA. The risk of further stroke in patients with symptomatic carotid stenosis is greatest within the first few weeks and rapidly reduces over the first 6 months.9
We hypothesised that a similar relation might exist with embolic signals; that is, their presence would be associated with an early high risk which would rapidly reduce over a period of weeks to months. For this reason, we assessed whether the presence of embolic signals at the start of each 6-month period predicted risk over the subsequent 6 months. This analysis confirmed associations between the presence of embolic signals and subsequent TIA and stroke risk, and there was also a significant association with the risk of any stroke and cardiovascular death. However, the difference in hazard ratios between prediction over 6 months and our primary analysis of prediction over 2 years was small and our results suggest that the presence of embolic signals is associated with risk over a longer follow-up period.
An important consideration with any risk stratification technique is whether it provides additional information over conventional risk factors. Controlling for whether the patient was treated with antiplatelet therapy, which was associated with the presence of embolic signals at baseline, did not markedly alter the association between embolic signals and future stroke risk. In addition, controlling for other risk factors that were specified in the study protocol17
but that were not associated with the presence of embolic signals at baseline had little effect on the associations with stroke and TIA or stroke alone. This supports the use of embolic signals as an independent predictor of stroke risk.
ACES is the first prospective, multicentre, international study of the predictive value of the detection of embolic signals. ACES included over 20 centres from different health-care systems, both academic and non-academic, and therefore its results are widely applicable. Analysis of embolic signals was done centrally by investigators who were masked to clinical information, and endpoint assessment was done centrally by investigators masked to the results of embolic signals analysis. There was only a small amount of missing data and no patients were lost to follow-up. There is a paucity of large multicentre studies evaluating the clinical impact of new neurovascular ultrasound techniques, which has resulted in uncertainty over their clinical application. However ACES, and other multicentre studies on embolic signal detection,14,24
and diagnostic ultrasound,26
show that such multicentre studies are feasible.
A potential limitation of ACES is that bias could have occurred in those cases of asymptomatic carotid stenosis where the surgeon was unwilling to enrol the patient, which could have led to exclusion of a higher risk group of patients. However, embolic signal results were not available at the time this decision was made and therefore would not have influenced the decision as to whether to enrol a patient in the study. A second limitation is that there were only ten strokes during follow-up, although there were 32 ipsilateral strokes or TIA.
If TCD is to be used as a clinical tool for risk stratification, improved methods of automated detection of embolic signals are needed. TCD recording itself is simple, non-invasive, and widely used in clinical practice worldwide. However, review of data for the presence of embolic signals is time consuming and relies on trained observers. Inter-observer reproducibility studies have reported that there is a high reproducibility among trained observers in detection of embolic signals, but that without adequate training some centres interpret the criteria incorrectly.27
The rate of embolisation we detected was low, with a median count of one per hour in those patients with embolic signals. Therefore, such automated systems need to be both sensitive and specific. Automated systems have been developed that have high sensitivity and specificity for detecting the higher intensity embolic signals seen in patients with symptomatic stenosis and in the immediate period after carotid endarterectomy.28
However, these systems were less sensitive to the lower intensity embolic signals found in asymptomatic carotid stenosis.29
Further work is needed to develop more sensitive systems, although there are several promising image analysis techniques that could be used in such systems. In our study we did all TCD recordings for 1 h. Further analysis of ACES data, and in particular an individual patient meta-analysis of studies to date, might allow us to identify the optimal duration of recording.
In summary, ACES shows that detection of embolic signals by TCD can identify groups of patients with asymptomatic carotid stenosis who are at low or high risk of future stroke. This technique might be a useful risk predictor for identifying those patients who might benefit from intervention with carotid endarterectomy.