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Asymptomatic carotid stenosis: What we can learn from the next generation of randomized clinical trials.

ABSTRACT: Stroke remains an exceedingly incident and prevalent public health burden across the globe, with an estimated 16 million new strokes per annum and prevalence over 60 million, and extracranial internal carotid artery atherosclerotic disease is an important risk factor for stroke. Randomized trials of surgical treatment were conducted (North American Symptomatic Carotid Endarterectomy Trial, European Carotid Surgery Trial) and demonstrated efficacy of carotid endarterectomy for secondary prevention of stroke in patients with cerebrovascular events (e.g. ipsilateral stroke, transient ischemic attack, and/or amaurosis fugax) attributable to a diseased artery with 50-99% stenosis. Therapeutic clarity, however, proved elusive with asymptomatic carotid artery disease. Asymptomatic Carotid Atherosclerosis Study (ACAS), Asymptomatic Carotid Surgery Trial, and Veterans Affairs Cooperative Study (VACS) suggested only modest benefit from surgical intervention for primary stroke prevention and the best medical therapy at the time of these trials is not comparable to modern medical therapy. ACT-1, Asymptomatic Carotid Surgery Trial-2, Stent-Protected Angioplasty in asymptomatic Carotid artery stenosis versus Endarterectomy Trial-2, European Carotid Surgery Trial-2, Carotid Revascularization Endarterectomy Versus Stenting Trial-2 are trials that are recent, ongoing, or in development that include diverse populations across Europe and North America, complementary trial designs, and a collaborative spirit that should provide clinicians with evidence that informs best clinical practice for asymptomatic carotid artery disease.

SUBMITTER: Rubin MN

PROVIDER: S-EPMC4157468 | biostudies-other | 2014 Jan

REPOSITORIES: biostudies-other

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Asymptomatic carotid stenosis: What we can learn from the next generation of randomized clinical trials.

Rubin Mark N MN Barrett Kevin M KM Brott Thomas G TG Meschia James F JF

JRSM cardiovascular disease 20140101

Stroke remains an exceedingly incident and prevalent public health burden across the globe, with an estimated 16 million new strokes per annum and prevalence over 60 million, and extracranial internal carotid artery atherosclerotic disease is an important risk factor for stroke. Randomized trials of surgical treatment were conducted (North American Symptomatic Carotid Endarterectomy Trial, European Carotid Surgery Trial) and demonstrated efficacy of carotid endarterectomy for secondary preventio ...[more]

PMID: 25247072

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Project description:Rationale Trials conducted decades ago demonstrated that carotid endarterectomy by skilled surgeons reduced stroke risk in asymptomatic patients. Developments in carotid stenting and improvements in medical prevention of stroke caused by atherothrombotic disease challenge understanding of the benefits of revascularization. Aim Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2) will test whether carotid endarterectomy or carotid stenting plus contemporary intensive medical therapy is superior to intensive medical therapy alone in the primary prevention of stroke in patients with high-grade asymptomatic carotid stenosis. Methods and design CREST-2 is two multicenter randomized trials of revascularization plus intensive medical therapy versus intensive medical therapy alone. One trial randomizes patients to carotid endarterectomy plus intensive medical therapy versus intensive medical therapy alone; the other, to carotid stenting plus intensive medical therapy versus intensive medical therapy alone. The risk factor targets of centrally directed intensive medical therapy are LDL cholesterol <70?mg/dl and systolic blood pressure <140?mmHg. Study outcomes The primary outcome is the composite of stroke and death within 44 days following randomization and stroke ipsilateral to the target vessel thereafter, up to four years. Change in cognition and differences in major and minor stroke are secondary outcomes. Sample size Enrollment of 1240 patients in each trial provides 85% power to detect a treatment difference if the event rate in the intensive medical therapy alone arm is 4.8% higher or 2.8% lower than an anticipated 3.6% rate in the revascularization arm. Discussion Management of asymptomatic carotid stenosis requires contemporary randomized trials to address whether carotid endarterectomy or carotid stenting plus intensive medical therapy is superior in preventing stroke beyond intensive medical therapy alone. Whether carotid endarterectomy or carotid stenting has favorable effects on cognition will also be tested. Trial registration United States National Institutes of Health Clinicaltrials.gov NCT02089217.

Project description:ObjectiveWe have shown that almost 50% of patients with asymptomatic carotid stenosis (ACS) will demonstrate cognitive impairment. Recent evidence has suggested that cerebral hypoperfusion is an important cause of cognitive impairment. Carotid stenosis can restrict blood flow to the brain, with consequent cerebral hypoperfusion. In contrast, cross-hemispheric collateral compensation through the Circle of Willis, and cerebrovascular vasodilation can also mitigate the effects of flow restriction. It is, therefore, critical to develop a clinically relevant measure of net brain perfusion in patients with ACS that could help in risk stratification and in determining the appropriate treatment. To determine whether ACS results in cerebral hypoperfusion, we developed a novel approach to quantify interhemispheric cerebral perfusion differences, measured as the time to peak (TTP) and mean transit time (MTT) delays using perfusion-weighted magnetic resonance imaging (PWI) of the whole brain. To evaluate the utility of using clinical duplex ultrasonography (DUS) to infer brain perfusion, we also assessed the relationship between the PWI findings and ultrasound-based peak systolic velocity (PSV).MethodsStructural and PWI of the brain and magnetic resonance angiography of the carotid arteries were performed in 20 patients with ≥70% ACS. DUS provided the PSV, and magnetic resonance angiography provided plaque geometric measures at the stenosis. Volumetric perfusion maps of the entire brain from PWI were analyzed to obtain the mean interhemispheric differences for the TTP and MTT delays. In addition, the proportion of brain volume that demonstrated a delay in TTP and MTT was also measured. These proportions were measured for increasing severity of perfusion delays (0.5, 1.0, and 2.0 seconds). Finally, perfusion asymmetries on PWI were correlated with the PSV and stenosis features on DUS using Pearson's correlation coefficients.ResultsOf the 20 patients, 18 had unilateral stenosis (8 right and 10 left) and 2 had bilateral stenoses. The interhemispheric (left-right) TTP delays measured for the whole brain volume identified impaired perfusion in the hemisphere ipsilateral to the stenosis in 16 of the 18 patients. More than 45% of the patients had had ischemia in at least one half of their brain volume, with a TTP delay >0.5 second. The TTP and MTT delays showed strong correlations with PSV. In contrast, the correlations with the percentage of stenosis were weaker. The correlations for the PSV were strongest with the perfusion deficits (TTP and MTT delays) measured for the whole brain using our proposed algorithm (r = 0.80 and r = 0.74, respectively) rather than when measured on a single magnetic resonance angiography slice as performed in current clinical protocols (r = 0.31 and r = 0.58, respectively).ConclusionsInterhemispheric TTP and MTT delay measured for the whole brain using PWI has provided a new tool for assessing cerebral perfusion deficits in patients with ACS. Carotid stenosis was associated with a detectable reduction in ipsilateral brain perfusion compared with the opposite hemisphere in >80% of patients. The PSV measured at the carotid stenosis using ultrasonography correlated with TTP and MTT delays and might serve as a clinically useful surrogate to brain hypoperfusion in these patients.

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Asymptomatic carotid stenosis: What we can learn from the next generation of randomized clinical trials.

Publications

Asymptomatic carotid stenosis: What we can learn from the next generation of randomized clinical trials.

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