Natan M. Bornstein

Mannheim carotid intima-media thickness consensus (2004-2006). An update on behalf of the Advisory Board of the 3rd and 4th Watching the Risk Symposium, 13th and 15th European Stroke Conferences, Mannheim, Germany, 2004, and Brussels, Belgium, 2006.

Intima-media thickness (IMT) is increasingly used as a surrogate end point of vascular outcomes in clinical trials aimed at determining the success of interventions that lower risk factors for atherosclerosis and associated diseases (stroke, myocardial infarction and peripheral artery diseases). The necessity to promote further criteria to distinguish early atherosclerotic plaque formation from thickening of IMT and to standardize IMT measurements is expressed through this updated consensus. Plaque is defined as a focal structure that encroaches into the arterial lumen of at least 0.5 mm or 50% of the surrounding IMT value or demonstrates a thickness >1.5 mm as measured from the media-adventitia interface to the intima-lumen interface. Standard use of IMT measurements is based on physics, technical and disease-related principles as well as agreements on how to perform, interpret and document study results. Harmonization of carotid image acquisition and analysis is needed for the comparison of the IMT results obtained from epidemiological and interventional studies around the world. The consensus concludes that there is no need to ‘treat IMT values’ nor to monitor IMT values in individual patients apart from exceptions named, which emphasize that inside randomized clinical trials should be performed. Although IMT has been suggested to represent an important risk marker, according to the current evidence it does not fulfill the characteristics of an accepted risk factor. Standardized methods recommended in this consensus statement will foster homogenous data collection and analysis. This will help to improve the power of randomized clinical trials incorporating IMT measurements and to facilitate the merging of large databases for meta-analyses.

Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke

BACKGROUND Recurrent stroke is a frequent, disabling event after ischemic stroke. This study compared the efficacy and safety of two antiplatelet regimens--aspirin plus extended-release dipyridamole (ASA-ERDP) versus clopidogrel. METHODS In this double-blind, 2-by-2 factorial trial, we randomly assigned patients to receive 25 mg of aspirin plus 200 mg of extended-release dipyridamole twice daily or to receive 75 mg of clopidogrel daily. The primary outcome was first recurrence of stroke. The secondary outcome was a composite of stroke, myocardial infarction, or death from vascular causes. Sequential statistical testing of noninferiority (margin of 1.075), followed by superiority testing, was planned. RESULTS A total of 20,332 patients were followed for a mean of 2.5 years. Recurrent stroke occurred in 916 patients (9.0%) receiving ASA-ERDP and in 898 patients (8.8%) receiving clopidogrel (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11). The secondary outcome occurred in 1333 patients (13.1%) in each group (hazard ratio for ASA-ERDP, 0.99; 95% CI, 0.92 to 1.07). There were more major hemorrhagic events among ASA-ERDP recipients (419 [4.1%]) than among clopidogrel recipients (365 [3.6%]) (hazard ratio, 1.15; 95% CI, 1.00 to 1.32), including intracranial hemorrhage (hazard ratio, 1.42; 95% CI, 1.11 to 1.83). The net risk of recurrent stroke or major hemorrhagic event was similar in the two groups (1194 ASA-ERDP recipients [11.7%], vs. 1156 clopidogrel recipients [11.4%]; hazard ratio, 1.03; 95% CI, 0.95 to 1.11). CONCLUSIONS The trial did not meet the predefined criteria for noninferiority but showed similar rates of recurrent stroke with ASA-ERDP and with clopidogrel. There is no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke. (ClinicalTrials.gov number, NCT00153062.)

Telmisartan to Prevent Recurrent Stroke and Cardiovascular Events

BACKGROUND Prolonged lowering of blood pressure after a stroke reduces the risk of recurrent stroke. In addition, inhibition of the renin-angiotensin system in high-risk patients reduces the rate of subsequent cardiovascular events, including stroke. However, the effect of lowering of blood pressure with a renin-angiotensin system inhibitor soon after a stroke has not been clearly established. We evaluated the effects of therapy with an angiotensin-receptor blocker, telmisartan, initiated early after a stroke. METHODS In a multicenter trial involving 20,332 patients who recently had an ischemic stroke, we randomly assigned 10,146 to receive telmisartan (80 mg daily) and 10,186 to receive placebo. The primary outcome was recurrent stroke. Secondary outcomes were major cardiovascular events (death from cardiovascular causes, recurrent stroke, myocardial infarction, or new or worsening heart failure) and new-onset diabetes. RESULTS The median interval from stroke to randomization was 15 days. During a mean follow-up of 2.5 years, the mean blood pressure was 3.8/2.0 mm Hg lower in the telmisartan group than in the placebo group. A total of 880 patients (8.7%) in the telmisartan group and 934 patients (9.2%) in the placebo group had a subsequent stroke (hazard ratio in the telmisartan group, 0.95; 95% confidence interval [CI], 0.86 to 1.04; P=0.23). Major cardiovascular events occurred in 1367 patients (13.5%) in the telmisartan group and 1463 patients (14.4%) in the placebo group (hazard ratio, 0.94; 95% CI, 0.87 to 1.01; P=0.11). New-onset diabetes occurred in 1.7% of the telmisartan group and 2.1% of the placebo group (hazard ratio, 0.82; 95% CI, 0.65 to 1.04; P=0.10). CONCLUSIONS Therapy with telmisartan initiated soon after an ischemic stroke and continued for 2.5 years did not significantly lower the rate of recurrent stroke, major cardiovascular events, or diabetes. (ClinicalTrials.gov number, NCT00153062.)

MANNHEIM CAROTID INTIMA-MEDIA THICKNESS AND PLAQUE CONSENSUS (2004–2006–2011)

Intima-media thickness (IMT) provides a surrogate end point of cardiovascular outcomes in clinical trials evaluating the efficacy of cardiovascular risk factor modification. Carotid artery plaque further adds to the cardiovascular risk assessment. It is defined as a focal structure that encroaches into the arterial lumen of at least 0.5 mm or 50% of the surrounding IMT value or demonstrates a thickness >1.5 mm as measured from the media-adventitia interface to the intima-lumen interface. The scientific basis for use of IMT in clinical trials and practice includes ultrasound physics, technical and disease-related principles as well as best practice on the performance, interpretation and documentation of study results. Comparison of IMT results obtained from epidemiological and interventional studies around the world relies on harmonization on approaches to carotid image acquisition and analysis. This updated consensus document delineates further criteria to distinguish early atherosclerotic plaque formation from thickening of IMT. Standardized methods will foster homogenous data collection and analysis, improve the power of randomized clinical trials incorporating IMT and plaque measurements and facilitate the merging of large databases for meta-analyses. IMT results are applied to individual patients as an integrated assessment of cardiovascular risk factors. However, this document recommends against serial monitoring in individual patients.

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.

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

BACKGROUND The treatment of ischaemic stroke with neuroprotective drugs has been unsuccessful, and whether these compounds can be used to reduce disability after recurrent stroke is unknown. The putative neuroprotective effects of antiplatelet compounds and the angiotensin II receptor antagonist telmisartan were investigated in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial. METHODS Patients who had had an ischaemic stroke were randomly assigned in a two by two factorial design to receive either 25 mg aspirin (ASA) and 200 mg extended-release dipyridamole (ER-DP) twice a day or 75 mg clopidogrel once a day, and either 80 mg telmisartan or placebo once per day. The predefined endpoints for this substudy were disability after a recurrent stroke, assessed with the modified Rankin scale (mRS) and Barthel index at 3 months, and cognitive function, assessed with the mini-mental state examination (MMSE) score at 4 weeks after randomisation and at the penultimate visit. Analysis was by intention to treat. The study was registered with ClinicalTrials.gov, number NCT00153062. FINDINGS 20,332 patients (mean age 66 years) were randomised and followed-up for a median of 2.4 years. Recurrent strokes occurred in 916 (9%) patients randomly assigned to ASA with ER-DP and 898 (9%) patients randomly assigned to clopidogrel; 880 (9%) patients randomly assigned to telmisartan and 934 (9%) patients given placebo had recurrent strokes. mRS scores were not statistically different in patients with recurrent stroke who were treated with ASA and ER-DP versus clopidogrel (p=0.38), or with telmisartan versus placebo (p=0.61). There was no significant difference in the proportion of patients with recurrent stroke with a good outcome, as measured with the Barthel index, across all treatment groups. Additionally, there was no significant difference in the median MMSE scores, the percentage of patients with an MMSE score of 24 points or less, the percentage of patients with a drop in MMSE score of 3 points or more between 1 month and the penultimate visit, and the number of patients with dementia among the treatment groups. There were no significant differences in the proportion of patients with cognitive impairment or dementia among the treatment groups. INTERPRETATION Disability due to recurrent stroke and cognitive decline in patients with ischaemic stroke were not different between the two antiplatelet regimens and were not affected by the preventive use of telmisartan.

Effectiveness and Safety of Transcranial Laser Therapy for Acute Ischemic Stroke

Background and Purpose— We hypothesized that transcranial laser therapy (TLT) can use near-infrared laser technology to treat acute ischemic stroke. The NeuroThera Effectiveness and Safety Trial–2 (NEST-2) tested the safety and efficacy of TLT in acute ischemic stroke. Methods— This double-blind, randomized study compared TLT treatment to sham control. Patients receiving tissue plasminogen activator and patients with evidence of hemorrhagic infarct were excluded. The primary efficacy end point was a favorable 90-day score of 0 to 2 assessed by the modified Rankin Scale. Other 90-day end points included the overall shift in modified Rankin Scale and assessments of change in the National Institutes of Health Stroke Scale score. Results— We randomized 660 patients: 331 received TLT and 327 received sham; 120 (36.3%) in the TLT group achieved favorable outcome versus 101 (30.9%), in the sham group (P=0.094), odds ratio 1.38 (95% CI, 0.95 to 2.00). Comparable results were seen for the other outcome measures. Although no prespecified test achieved significance, a post hoc analysis of patients with a baseline National Institutes of Health Stroke Scale score of <16 showed a favorable outcome at 90 days on the primary end point (P<0.044). Mortality rates and serious adverse events did not differ between groups with 17.5% and 17.4% mortality, 37.8% and 41.8% serious adverse events for TLT and sham, respectively. Conclusions— TLT within 24 hours from stroke onset demonstrated safety but did not meet formal statistical significance for efficacy. However, all predefined analyses showed a favorable trend, consistent with the previous clinical trial (NEST-1). Both studies indicate that mortality and adverse event rates were not adversely affected by TLT. A definitive trial with refined baseline National Institutes of Health Stroke Scale exclusion criteria is planned.

Is Impaired Cerebral Vasomotor Reactivity a Predictive Factor of Stroke in Asymptomatic Patients

BACKGROUND AND PURPOSE Identification of the subgroup of asymptomatic patients with severe internal carotid artery stenosis and high risk of stroke has important clinical implications. Cerebral vasomotor reactivity provides information regarding intracranial hemodynamic features and might have a prognostic value in predicting cerebrovascular ischemic events, especially in patients with carotid stenosis. The aim of our study was to assess the cerebral vasomotor reactivity in asymptomatic patients with carotid stenosis and evaluate its role in stroke occurrence. METHODS Cerebral vasomotor reactivity was assessed using transcranial Doppler ultrasonology and the Diamox test (intravenous administration of 1.0 g acetazolamide) in 44 asymptomatic patients with severe (> 70%) internal carotid artery stenosis. Patients were followed up prospectively (mean, 2 years). RESULTS Cerebral vasomotor reactivity was estimated as good (> 40% increase of blood flow velocity in the middle cerebral artery ipsilateral to the carotid stenosis after undergoing the Diamox test) in 23 patients; it was impaired in the other 21. During the follow-up period, the overall annual rate for ipsilateral stokes was 2.3%; it was 7.9% for all ischemic cerebral events. No strokes or transient ischemic attacks occurred in the former group, but there were 7 cerebral ischemic events (2 strokes [1 fatal] and 5 transient ischemic attacks) in the latter group. There was a statistically significant correlation between cerebral ischemic events and impaired cerebral vasomotor reactivity (P = .009). CONCLUSIONS The data of this preliminary study suggest an important role of impaired cerebral vasomotor reactivity in predicting ischemic cerebral events. Preventive vascular surgery might be considered in this high-risk subgroup of asymptomatic patients with severe carotid stenosis.

Acute Infection as a Risk Factor for Ischemic Stroke

BACKGROUND AND PURPOSE Prior studies have demonstrated that infections might precipitate ischemic strokes (IS), but the role of infection as a risk factor remains unclear. We conducted a case-control study to investigate this issue. METHODS Consecutive patients (n = 182) with acute IS were examined within 48 hours after admission to our center. A history of acute infections within 2 months before the IS was assessed by means of a specially designed questionnaire that was also given to a control group consisting of 194 consecutive patients who were seen in our outpatient clinic and had suffered IS at least 6 months previously. RESULTS The prevalence of acute infection in the study group was significantly higher (44/182 = 24.2%) than in the control group (19/194 = 9.7%; odds ratio, 2.93; 95% confidence interval, 1.64 to 5.26; P = .0002) and infection occurred mostly within 1 week before the IS (41/44). Neither the severity of the IS nor the type of the infection was significantly different in patients and control subjects. CONCLUSIONS Acute infections of different types constitute a risk factor for IS, particularly within 1 week of the event. However, the severity of the stroke is not related to this factor.

ACE, MTHFR, Factor V Leiden, and APOE Polymorphisms in Patients With Vascular and Alzheimer’s Dementia

BACKGROUND AND PURPOSE There is a growing interest in the use of genetic markers in the differential diagnosis of dementia. In the current study we examined the usefulness of genetic risk factors for vascular disease as markers for vascular dementia (VD). METHODS The groups included 41 patients with VD, 49 patients with dementia of the Alzheimers type, and 40 age-matched control subjects without dementia. These patients were genotyped for vascular disease-associated polymorphisms in the genes coding for methylenetetrahydrofolate reductase (MTHFR), angiotensin-converting enzyme (ACE), factor V Leiden (FVL), and a common genetic risk factor for AD, apolipoprotein E epsilon4 (APOE epsilon4). RESULTS There was no significant association between ACE, MTHFR, and FVL genotypes with VD whether compared with subjects with AD or with control subjects. There was a higher frequency of APOE epsilon4 alleles in patients with AD (30%, P=0.016) and VD (26%, P=0.07) compared with control subjects (15%). CONCLUSIONS VD is not associated with the genetic risk factors for vascular disease examined in this study, indicating that the pathogenesis of VD may differ from other vascular diseases.