Chimowitz, Marc I.

Background: The importance of physical activity in preventing major vascular events has received increased attention in the past decade. Due to the inclusion of the INTERVENT lifestyle modification program, the CREST2 trial provides a unique opportunity to study physical activity profiles in patients with severe asymptomatic extracranial carotid stenosis. Hypothesis: Based on data from a trial of intracranial stenosis patients, we aimed to evaluate the hypothesis that <40% of carotid stenosis subjects will have optimal physical activity levels. We also assessed key subgroups to determine patterns of physical activity. Methods: We analyzed 1087 CREST2 participants with baseline data on physical activity. The Physician-based Assessment and Counseling for Exercise (PACE) score is recorded for each patient and dichotomized as “in target” (4-8 points) or “out of target” (<4 points). A PACE score of <4 indicates a subject who does not engage in regular exercise. Results are analyzed for the entire trial. Chi square testing and t-tests were performed for evaluation of subgroup differences. Results: The mean age of the study population is 69.5±7.8 years (60% male). The median PACE score at baseline is 4.0 (mean 3.8±2.1; IQR 2 to 6). The Table shows baseline characteristics of patients by mean PACE score. Being male, not having diabetes mellitus, having a body mass index <30kg/m2, being a non-smoker, and not having a history of peripheral arterial disease were associated with significantly higher mean PACE scores (P<0.01). Conclusions: We have defined several patient groups with asymptomatic carotid stenosis that have suboptimal physical activity. These results provide opportunities for targeted efforts to improve primary stroke prevention. These baseline data will also allow investigators to determine if trial involvement and the INTERVENT program leads to improvement in the level of physical activity.

Background: In CREST2, intensive medical management of subjects’ vascular risk factors is overseen by the site Principal Investigator (PI) and implemented by a designated Medical Management Physician (MMP) and coordinator. These physicians have different specialties and experience with risk factor management. We sought to determine the relationship between risk factor control and PI and MMP specialty. Methods: Data on 613 patients with at least 1 follow-up visit from 105 CREST2 sites were used for these analyses. CREST2 sites were categorized based on both PI specialty and MMP specialty. Specialty of the site-designated primary MMP was used for sites with more than one MMP. We compared the percentage of patients in target at last follow-up visit for the primary risk factors, LDL < 70 mg/dL and SBP <140 mm Hg, among PI specialties and MMP specialties, using the chi-square test. Results: The table shows the number of patients by PI and MMP specialty, as well as their control of SBP and LDL. There were no significant differences in control of SBP or LDL by PI specialty. There was a trend toward an association between LDL control and MMP specialty, with higher rates of LDL control at sites with Internal Medicine MMP specialists and lower rates of control with Vascular Surgery MMPs. SBP control rates were not significantly different across MMP specialties. Conclusions: In this early analysis of risk factor control in the CREST2 study, site PI and MMP specialty did not have a significant effect on LDL and SBP during follow-up. This suggests that protocol care pathways are generalizable to diverse physicians.

OBJECTIVE Clinical vasospasm and delayed cerebral ischemia (DCI) are devastating complications of aneurysmal subarachnoid hemorrhage (aSAH). Several theories involving platelet activation have been postulated as potential explanations of the development of clinical vasospasm and DCI. However, the effects of dual antiplatelet therapy (DAPT; aspirin and clopidogrel) on clinical vasospasm and DCI have not been previously investigated. The objective of this study was to evaluate the effects of DAPT on clinical vasospasm and DCI in aSAH patients. METHODS Analysis of patients treated for aSAH during the period from July 2009 to April 2014 was performed in a single-institution retrospective study. Patients were divided into 2 groups: patients who underwent stent-assisted coiling or placement of flow diverters requiring DAPT (DAPT group) and patients who underwent coiling only without DAPT (control group). The frequency of symptomatic clinical vasospasm and DCI and of hemorrhagic complications was compared between the 2 groups, utilizing univariate and multivariate logistic regression. RESULTS Of 312 aSAH patients considered for this study, 161 met the criteria for inclusion and were included in the analysis (85 patients in the DAPT group and 76 patients in the control group). The risks of clinical vasospasm (OR 0.244, CI 95% 0.097–0.615, p = 0.003) and DCI (OR 0.056, CI 95% 0.01–0.318, p = 0.001) were significantly lower in patients receiving DAPT. The rates of hemorrhagic complications associated with placement of external ventricular drains and ventriculoperitoneal shunts were similar in both groups (4% vs 2%, p = 0.9). CONCLUSIONS The use of DAPT was associated with a lower risk of clinical vasospasm and DCI in patients treated for aSAH, without an increased risk of hemorrhagic complications.

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

Collateral circulation in intracranial atherosclerosis has never been systematically characterized. We investigated collaterals in a multicenter trial of symptomatic intracranial atherosclerotic disease. Baseline angiography was reviewed for information on collaterals in stenoses of the internal carotid, middle cerebral, vertebral, and basilar arteries. A battery of angiographic scales was utilized to evaluate lesion site, arterial patency, antegrade flow, downstream territorial perfusion, and collateral circulation, blinded to all other data. Collateral circulation was adequately available for analysis in 287/569 (50%) subjects with proximal arterial stenoses ranging from 50% to 99%. Extent of collaterals was absent or none in 69%, slow or minimal in 10%, more rapid, yet incomplete perfusion of territory in 7%, complete but delayed perfusion in 11%, and rapid, complete collateral perfusion in 4%. Extent of collateral flow correlated with percentage of stenosis ( P < 0.0001), with more severe stenoses exhibiting greater compensation via collaterals. Overall, collateral grade increased with diminished antegrade flow across the lesion (thrombolysis in myocardial ischemia) and resultant downstream perfusion (thrombolysis in cerebral infarction) (both P<0.001). Our findings provide the initial detailed description of collaterals across a variety of stenoses, suggesting that collateral perfusion is a pivotal component in pathophysiology of intracranial atherosclerosis and implicating the need for further evaluation in ongoing studies.

Background and Purpose— We sought to determine the vascular risk factors and demographic features associated with the severity and location of intracranial stenosis. Methods— Data on patients enrolled in the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial were used for the analyses. Demographic features and vascular risk factors were compared in patients with moderate stenosis (n=336) versus severe stenosis (n=225) and according to the location of intracranial stenosis (middle cerebral, internal carotid, basilar, or vertebral artery). Results— History of a lipid disorder (77% in severe vs 67% in moderate, P =0.01), metabolic syndrome (63% in severe vs 53% in moderate, P =0.05), and diabetes (43% in severe vs 35% in moderate, P =0.04) were more common in patients with severe intracranial stenosis by univariate analyses. A history of a lipid disorder was independently associated with severe stenosis (odds ratio=1.62; 95% CI, 1.09 to 2.42; P =0.02). The distribution of stenosis location differed among age groups ( P =0.0015), sexes ( P =0.0001), races ( P =0.0243), qualifying events ( P =0.0156), diabetes ( P =0.0030), coronary artery disease ( P =0.0030), and hyperlipidemia ( P =0.054). Patients with basilar artery stenoses were older and more likely to have hyperlipidemia. Patients with middle cerebral artery stenoses were more likely to be women and black. Patients with internal carotid artery stenoses were more likely to have diabetes. Patients with vertebral artery stenoses were more likely to have coronary artery disease. Conclusions— History of a lipid disorder had the strongest association with severity of intracranial stenosis and should be the target of prevention therapies. Different locations of intracranial stenoses are associated with different vascular risk factors and demographic features, suggesting that there may be a difference in the underlying pathophysiology of stenoses among the intracranial arteries.