Alice King

Asymptomatic embolisation for prediction of stroke in the Asymptomatic Carotid Emboli Study (ACES): a prospective observational study

Summary Background Whether surgery is beneficial for patients with asymptomatic carotid stenosis is controversial. Better methods of identifying patients who are likely to develop stroke would improve the risk–benefit ratio for carotid endarterectomy. We aimed to investigate whether detection of asymptomatic embolic signals by use of transcranial doppler (TCD) could predict stroke risk in patients with asymptomatic carotid stenosis. Methods The Asymptomatic Carotid Emboli Study (ACES) was a prospective observational study in patients with asymptomatic carotid stenosis of at least 70% from 26 centres worldwide. To detect the presence of embolic signals, patients had two 1 h TCD recordings from the ipsilateral middle cerebral artery at baseline and one 1 h recording at 6, 12, and 18 months. Patients were followed up for 2 years. The primary endpoint was ipsilateral stroke and transient ischaemic attack. All recordings were analysed centrally by investigators masked to patient identity. Findings 482 patients were recruited, of whom 467 had evaluable recordings. Embolic signals were present in 77 of 467 patients at baseline. The hazard ratio for the risk of ipsilateral stroke and transient ischaemic attack from baseline to 2 years in patients with embolic signals compared with those without was 2·54 (95% CI 1·20–5·36; p=0·015). For ipsilateral stroke alone, the hazard ratio was 5·57 (1·61–19·32; p=0·007). The absolute annual risk of ipsilateral stroke or transient ischaemic attack between baseline and 2 years was 7·13% in patients with embolic signals and 3·04% in those without, and for ipsilateral stroke was 3·62% in patients with embolic signals and 0·70% in those without. The hazard ratio for the risk of ipsilateral stroke and transient ischaemic attack for patients who had embolic signals on the recording preceding the next 6-month follow-up compared with those who did not was 2·63 (95% CI 1·01–6·88; p=0·049), and for ipsilateral stroke alone the hazard ratio was 6·37 (1·59–25·57; p=0·009). Controlling for antiplatelet therapy, degree of stenosis, and other risk factors did not alter the results. Interpretation Detection of asymptomatic embolisation on TCD can be used to identify patients with asymptomatic carotid stenosis who are at a higher risk of stroke and transient ischaemic attack, and also those with a low absolute stroke risk. Assessment of the presence of embolic signals on TCD might be useful in the selection of patients with asymptomatic carotid stenosis who are likely to benefit from endarterectomy. Funding British Heart Foundation.

Circulating MicroRNAs as Novel Biomarkers for Platelet Activation

Rationale: MicroRNA (miRNA) biomarkers are attracting considerable interest. Effects of medication, however, have not been investigated thus far. Objective: To analyze changes in plasma miRNAs in response to antiplatelet therapy. Methods and Results: Profiling for 377 miRNAs was performed in platelets, platelet microparticles, platelet-rich plasma, platelet-poor plasma, and serum. Platelet-rich plasma showed markedly higher levels of miRNAs than serum and platelet-poor plasma. Few abundant platelet miRNAs, such as miR-24, miR-197, miR-191, and miR-223, were also increased in serum compared with platelet-poor plasma. In contrast, antiplatelet therapy significantly reduced miRNA levels. Using custom-made quantitative real-time polymerase chain reaction plates, 92 miRNAs were assessed in a dose-escalation study in healthy volunteers at 4 different time points: at baseline without therapy, at 1 week with 10 mg prasugrel, at 2 weeks with 10 mg prasugrel plus 75 mg aspirin, and at 3 weeks with 10 mg prasugrel plus 300 mg aspirin. Findings in healthy volunteers were confirmed by individual TaqMan quantitative real-time polymerase chain reaction assays (n=9). Validation was performed in an independent cohort of patients with symptomatic atherosclerosis (n=33), who received low-dose aspirin at baseline. Plasma levels of platelet miRNAs, such as miR-223, miR-191, and others, that is, miR-126 and miR-150, decreased on further platelet inhibition. Conclusions: Our study demonstrated a substantial platelet contribution to the circulating miRNA pool and identified miRNAs responsive to antiplatelet therapy. It also highlights that antiplatelet therapy and preparation of blood samples could be confounding factors in case-control studies relating plasma miRNAs to cardiovascular disease.

Ultrasonic plaque echolucency and emboli signals predict stroke in asymptomatic carotid stenosis

Objectives: Better methods are required to identify patients with asymptomatic carotid stenosis (ACS) at risk of future stroke. Two potential markers of high risk are echolucent plaque morphology on carotid ultrasound and embolic signals (ES) in the ipsilateral middle cerebral artery on transcranial Doppler ultrasound (TCD). We explored the predictive value of a score based on these 2 measures in the prospective, observational, international multicenter Asymptomatic Carotid Emboli Study. Methods: A total of 435 recruited subjects with ACS ≥70% had baseline ultrasound images and TCD data available. Subjects were prospectively followed up for 2 years. Results: A total of 164 (37.7%) plaques were graded as echolucent. Plaque echolucency at baseline was associated with an increased risk of ipsilateral stroke alone (hazard ratio [HR] 6.43, 95% confidence interval [CI] 1.36–30.44, p = 0.019). A combined variable of plaque echolucency and ES positivity at baseline was associated with a markedly increased risk of ipsilateral stroke alone (HR 10.61, 95% CI 2.98–37.82, p = 0.0003). This association remained significant after controlling for risk factors, degree of carotid stenosis, and antiplatelet medication. Conclusions: Plaque morphology assessed using a simple, and clinically applicable, visual rating scale predicts ipsilateral stroke risk in ACS. The combination of ES detection and plaque morphology allows a greater prediction than either measure alone and identifies a high-risk group with an annual stroke risk of 8%, and a low-risk group with a risk of <1% per annum. This risk stratification may prove useful in the selection of patients with ACS for endarterectomy. Neurology® 2011;77:751–758

Doppler Embolic Signals in Cerebrovascular Disease and Prediction of Stroke Risk: A Systematic Review and Meta-Analysis

Background and Purpose— Asymptomatic embolic signals (ES) detected using transcranial Doppler have been reported in patients with potential cerebral embolic sources. They may be useful in risk stratification and in assessing therapies. First, it is essential to show whether they predict stroke risk. Methods— A systematic review and meta-analysis was performed to determine the prognostic value of ES in different potential cerebral embolic sources. Studies were identified that used transcranial Doppler to detect ES and included prospective stroke/TIA follow-up. Numbers of ES-positive and ES-negative patients were extracted with stroke/TIA and stroke alone outcomes. Results— ES are most frequent in large artery disease, less frequent in cardioembolic stroke, and infrequent in lacunar stroke. Data relating ES to future stroke risk were available for acute stroke, large artery disease, and the perioperative period of carotid endarterectomy. For symptomatic carotid stenosis, ES predicted stroke alone (OR, 9.57; 95%CI, 1.54 to 59.38; P=0.02) and stroke/TIA (OR, 6.36; 95% CI, 2.90–13.96; P<0.00001). For asymptomatic carotid stenosis, ES predicted stroke alone (OR, 7.46; 95% CI, 2.24–24.89; P=0.001) and stroke/TIA (OR, 12.00; 95% CI, 2.43–59.34; P=0.002) but with heterogeneity (P=0.004). In acute stroke ES predicted stroke alone (OR, 2.44; 95% CI, 1.17–5.08; P=0.02) and stroke/TIA (OR, 3.71; 95% CI, 1.64–8.38; P=0.002). A high frequency of ES immediately after carotid endarterectomy predicted stroke alone (OR, 24.54; 95% CI, 7.88–76.43; P<0.00001) and stroke/TIA (OR, 32.04; 95% CI, 11.36–90.39; P<0.00001). Conclusion— ES predict stroke risk in acute stroke, symptomatic carotid stenosis, and postoperatively after carotid endarterectomy; in asymptomatic carotid stenosis, data are less robust. In these conditions ES may be useful in risk stratification and in assessing therapeutic efficacy. For other embolic sources, further prospective data are required.

The von Willebrand Inhibitor ARC1779 reduces cerebral embolization after carotid endarterectomy : a randomized trial

Background and Purpose— Inhibition of von Willebrand factor offers a novel approach to prevention of stroke and myocardial ischemia but has not yet been demonstrated to show efficacy on clinically relevant end points. ARC1779 is an aptamer that inhibits the prothrombotic function of von Willebrand factor by binding to the A1 domain of von Willebrand factor and thereby blocking its interaction with glycoprotein. Phase 1 studies suggest it inhibits platelet aggregation with less increase in bleeding than conventional antiplatelet agents. The effect of ARC 1779 on cerebral emboli immediately after carotid endarterectomy was investigated in a randomized clinical trial. Methods— Patients undergoing carotid endarterectomy were randomized double-blind to ARC1779 or placebo administered intravenously. Transcranial Doppler recording, to detect cerebral embolic signals, was performed in the first 3 hours postoperatively. The primary end point was time to first embolic signals. Results— Thirty-six patients were recruited, 18 in each arm. The Kaplan-Meier median time to first embolic signals was 83.6 minutes for ARC1779 compared with 5.5 minutes for placebo. Using Cox proportional hazards embolic signals occurred statistically significantly later on ARC1779 (P=0.007). Reduced embolic signals counts were correlated with inhibition of von Willebrand factor activity (P=0.03). Increased perioperative bleeding and anemia were seen with ARC1779. Conclusions— von Willebrand factor inhibition reduces thromboembolism in humans. It may play a role in treatment of stroke and myocardial ischemia. The extent to which bleeding complications occur in nonoperated patients needs to be assessed in further studies. Clinical Trial Registration— URL: http://clinicaltrials.gov. Unique identifier: NCT00742612.

Does Impaired Cerebrovascular Reactivity Predict Stroke Risk in Asymptomatic Carotid Stenosis?: A Prospective Substudy of the Asymptomatic Carotid Emboli Study

Background and Purpose— Improved methods are required to identify the subgroup of patients with asymptomatic carotid stenosis who will have stroke develop. It has been suggested that impaired cerebral reactivity (CVR) may predict high risk, but no multicenter studies have examined this. Methods— In a preplanned substudy of Asymptomatic Carotid Emboli Study, 106 patients were recruited with ≥70% asymptomatic carotid stenosis. Transcranial Doppler was used to measure CVR with a vasodilatory response of carbon dioxide or acetazolamide. A meta-analysis of the data with previously published studies was performed. Results— Thirty-two of 106 (30.2%) had severely impaired CVR ipsilateral to the study artery. Mean follow-up was 680 days. There were no ipsilateral strokes. There was a nonsignificant trend to more secondary end points of any stroke/TIA in patients with severely impaired CVR. Three of 32 (9.4%) had impaired CVR compared with 2 of 74 (2.7%) without (hazard ratio, 2.54; 95% CI, 0.61–21.74; P=0.158). On meta-analysis of the Asymptomatic Carotid Emboli Study data with previous studies, impaired CVR was associated with increased risk of ipsilateral stroke alone (OR, 6.14; 95% CI, 1.27–29.5; P=0.02), ipsilateral stroke or TIA (OR, 4.76; 95% CI, 1.86–12.16; P=0.001), and any stroke (OR, 4.66; 95% CI, 1.69–12.85; P=0.003). Conclusions— In this international multicenter study, we found no association between impaired CVR and recurrent events, but the study was underpowered because of the low event rate. Meta-analysis of available data suggested an association between impaired CVR and future risk. However, currently there are insufficient data to justify the routine clinical use of CVR to stratify risk in patients with asymptomatic carotid stenosis for selection for carotid endarterectomy.

Cerebrovascular reactivity predicts stroke in high-grade carotid artery disease

Objective: To assess the usefulness of transcranial Doppler CO2 reactivity (CO2R) for prediction of ipsilateral ischemic stroke in carotid artery stenosis and occlusion with a meta-analysis of prospective studies based on individual patient data. Methods: We searched Medline, Biosis Previews, Science Citation Index, The Cochrane Library, and EMBASE for studies in which patients with severe carotid artery stenosis or occlusion underwent Doppler CO2R testing (inhalation of CO2 or breath-holding) and were prospectively followed for ipsilateral ischemic stroke. Individual data from 754 patients from 9 studies were included. We used percentage cerebral blood flow velocity increase (pCi) during hypercapnia as the primary CO2R measure, and defined impaired reactivity as pCi <20% increase. Results: In a multiple regression model, impaired CO2R was independently associated with an increased risk of ipsilateral ischemic stroke (hazard ratio [HR] 3.69; confidence interval [CI] 2.01, 6.77; p < 0.0001). Risk prediction was similar for recently symptomatic vs asymptomatic patients. Using continuous values of pCi, a significant association between decreasing pCi and increasing risk of ipsilateral stroke was found: HR of 1.64 (95% CI 1.33, 2.02; p < 0.0001) per 10% decrease in pCi. For patients with asymptomatic internal carotid artery stenosis only (n = 330), a comparable stroke risk prediction was found: increasing HR 1.95 (95% CI 1.26, 3.04; p = 0.003) per 10% decrease in pCi. Conclusions: This analysis supports the usefulness of CO2R in risk prediction for patients with severe carotid artery stenosis or occlusion, both in recently symptomatic and asymptomatic patients. Further studies should evaluate whether treatment strategies in asymptomatic patients based on CO2R could improve patient outcomes.

Clopidogrel Versus Dipyridamole in Addition to Aspirin in Reducing Embolization Detected With Ambulatory Transcranial Doppler A Randomized Trial

Background and Purpose— After stroke and transient ischemic attack there is a high early risk of recurrent stroke, particularly in large artery disease. It has been suggested more intensive antiplatelet regimens are required, but trial data are lacking. Treatment efficacy can be evaluated using transcranial Doppler detection of embolic signals. Ambulatory transcranial Doppler has recently been developed; prolonged recording may reduce subject numbers required to determine therapeutic efficacy. In a randomized trial (ISRCTN68019845) with blinded end point evaluation, we determined whether treatment with dipyridamole or clopidogrel, in addition to aspirin, was more effective at reducing embolization. Methods— Consecutive patients with recent symptomatic carotid stenosis were recruited. Ambulatory transcranial Doppler and platelet aggregometry were performed at baseline and 48 hours. Patients, all on aspirin, were randomized to dipyridamole or clopidogrel. Recordings were analyzed offline masked to subject identity. Results— Sixty patients were recruited, 30 in each arm. The primary end point of change in embolic signal frequency did not differ between groups (P=0.36). In patients with embolic signals at baseline, there was no difference in reduction in embolic signal frequency: dipyridamole (75.5; SD 17.7%) versus clopidogrel (77.5; SD 20.5%; P=0.77). Baseline platelet aggregation was not different between regimens, but at 48 hours, adenosine 5′-diphosphate aggregation rate (but not collagen) was lower with clopidogrel (P<0.001). Conclusions— Both dipyridamole and clopidogrel reduced embolization to a similar extent. Embolic signals are strong predictors of future stroke rate in this patient group. Our results suggest these 2 treatment regimens have similar efficacy in early secondary prevention of stroke, although this now needs testing in large Phase III trials.

Optimizing Protocols for Risk Prediction in Asymptomatic Carotid Stenosis Using Embolic Signal Detection The Asymptomatic Carotid Emboli Study

Background and Purpose— Improved methods are required to identify patients with asymptomatic carotid stenosis at high risk for stroke. The Asymptomatic Carotid Emboli Study recently showed embolic signals (ES) detected by transcranial Doppler on 2 recordings that lasted 1-hour independently predict 2-year stroke risk. ES detection is time-consuming, and whether similar predictive information could be obtained from simpler recording protocols is unknown. Methods— In a predefined secondary analysis of Asymptomatic Carotid Emboli Study, we looked at the temporal variation of ES. We determined the predictive yield associated with different recording protocols and with the use of a higher threshold to indicate increased risk (≥2 ES). To compare the different recording protocols, sensitivity and specificity analyses were performed using analysis of receiver-operator characteristic curves. Results— Of 477 patients, 467 had baseline recordings adequate for analysis; 77 of these had ES on 1 or both of the 2 recordings. ES status on the 2 recordings was significantly associated (P<0.0001), but there was poor agreement between ES positivity on the 2 recordings (&kgr;=0.266). For the primary outcome of ipsilateral stroke or transient ischemic attack, the use of 2 baseline recordings lasting 1 hour had greater predictive accuracy than either the first baseline recording alone (P=0.0005), a single 30-minute (P<0.0001) recording, or 2 recordings lasting 30 minutes (P<0.0001). For the outcome of ipsilateral stroke alone, two recordings lasting 1 hour had greater predictive accuracy when compared to all other recording protocols (all P<0.0001). Conclusions— Our analysis demonstrates the relative predictive yield of different recording protocols that can be used in application of the technique in clinical practice. Two baseline recordings lasting 1 hour as used in Asymptomatic Carotid Emboli Study gave the best risk prediction.

Prognosis of carotid dissecting aneurysms: Results from CADISS and a systematic review

Objective: To determine the natural history of dissecting aneurysm (DA) and whether DA is associated with an increased recurrent stroke risk and whether type of antithrombotic drugs (antiplatelets vs anticoagulants) modifies the persistence or development of DA. Methods: We included 264 patients with extracranial cervical artery dissection (CAD) from the Cervical Artery Dissection in Stroke Study (CADISS), a multicenter prospective study that compared antiplatelet with anticoagulation therapy. Logistic regression was used to estimate age- and sex-adjusted odds ratios. We conducted a systematic review of published studies assessing the natural history of DA and stroke risk in patients with non-surgically-treated extracranial CAD with DA. Results: In CADISS, DA was present in 24 of 264 patients at baseline. In 36 of 248 patients with follow-up neuroimaging at 3 months, 12 of the 24 baseline DAs persisted, and 24 new DA had developed. There was no association between treatment allocation (antiplatelets vs anticoagulants) and whether DA at baseline persisted at follow-up or whether new DA developed. During 12 months of follow-up, stroke occurred in 1 of 48 patients with DA and in 7 of 216 patients without DA (age- and sex-adjusted odds ratio 0.84; 95% confidence interval 0.10–7.31; p = 0.88). Published studies, mainly retrospective, showed a similarly low risk of stroke and no evidence of an increased stroke rate in patients with DA. Conclusions: The results of CADISS provide evidence suggesting that DAs may have benign prognosis and therefore medical treatment should be considered.