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Background and Purpose— Established risk factors do not fully identify patients at risk for recurrent stroke. The SPARCL trial (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) evaluated the effect of atorvastatin on stroke risk in patients with a recent stroke or transient ischemic attack and no known coronary heart disease. This analysis explored the relationships between 13 plasma biomarkers assessed at trial enrollment and the occurrence of outcome strokes. Methods— We conducted a case–cohort study of 2176 participants; 562 had outcome strokes and 1614 were selected randomly from those without outcome strokes. Time to stroke was evaluated by Cox proportional hazards models. Results— There was no association between time to stroke and lipoprotein-associated phospholipase A 2 , monocyte chemoattractant protein-1, resistin, matrix metalloproteinase-9, N-terminal fragment of pro-B-type natriuretic peptide, soluble vascular cell adhesion molecule-1, soluble intercellular adhesion molecule-1, or soluble CD40 ligand. In adjusted analyses, osteopontin (hazard ratio per SD change, 1.362; P P =0.0107), myeloperoxidase (hazard ratio, 1.177; P =0.0022), and adiponectin (hazard ratio, 1.207; P =0.0013) were independently associated with outcome strokes. After adjustment for the Stroke Prognostic Instrument-II and treatment, osteopontin, neopterin, and myeloperoxidase remained independently associated with outcome strokes. The addition of these 3 biomarkers to Stroke Prognostic Instrument-II increased the area under the receiver operating characteristic curve by 0.023 ( P =0.015) and yielded a continuous net reclassification improvement (29.1%; P P Conclusions— Osteopontin, neopterin, and myeloperoxidase were independently associated with the risk of recurrent stroke and improved risk classification when added to a clinical risk algorithm. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique Identifier: NCT00147602.

Background and Purpose— Higher low-density lipoprotein cholesterol is associated with more rapid chronic kidney disease progression; reduction in cholesterol with statins, in conjunction with statins’ pleiotropic effects, such as decreasing inflammation, may be renoprotective. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial assessed the effect of statin treatment on the risk of nonfatal and fatal stroke in subjects with a noncardioembolic stroke or transient ischemic attack, no known coronary heart disease, and low-density lipoprotein cholesterol between 2.6 and 4.9 mmol/L (100–190 mg/dL). Methods— We explored the effect of randomization to atorvastatin 80 mg/d or placebo on the change in estimated glomerular filtration rate (eGFR; using the 4-component Modification of Diet in Renal Disease Study equation) in SPARCL subjects (n=4731) with (eGFR, 2 ; n=3119) and without (eGFR, ≥60 mL/min per 1.73 m 2 ; n=1600) chronic kidney disease overall and by glycemic status at baseline. Results— Mean baseline eGFR was similar between treatment groups (65.5±0.26 versus 65.6±0.26 mL/min per 1.73 m 2 atorvastatin versus placebo; 33% versus 34% had chronic kidney disease, respectively; P =0.55). After 60 months, eGFR increased 3.46±0.33 mL/min per 1.73 m 2 in those randomized to atorvastatin versus 1.42±0.34 mL/min per 1.73 m 2 in those randomized to placebo ( P 2 in the atorvastatin group and decreased 1.69±0.92 mL/min per 1.73 m 2 in placebo group during a period of 60 months ( P =0.016). Conclusions— This post hoc analysis suggests that atorvastatin treatment may improve renal function in patients with prior stroke or transient ischemic attack with and without chronic kidney disease, and that atorvastatin treatment may prevent eGFR decline in patients with stroke and diabetes mellitus. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00147602.

Background and Purpose— Noncoronary forms of atherosclerosis (including transient ischemic attacks or stroke of carotid origin or >50% stenosis of the carotid artery) are associated with a 10-year vascular risk of >20% and are considered as a coronary heart disease (CHD) -risk equivalent from the standpoint of lipid management. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial included patients with stroke or transient ischemic attack and no known CHD regardless of the presence of carotid atherosclerosis. We evaluated the risk of developing clinically recognized CHD in SPARCL patients. Methods— A total of 4731 patients (mean age, 63 years) was randomized to 80 mg/day atorvastatin placebo. The rates of major coronary event, any CHD event, and any revascularization procedure were evaluated. Results— After 4.9 years of follow-up, the risks of a major coronary event and of any CHD end point in the placebo group were 5.1% and 8.6%, respectively. The rate of outcome of stroke decreased over time, whereas the major coronary event rate was stable. Relative to those having a large vessel-related stroke at baseline, those having a transient ischemic attack, hemorrhagic stroke, small vessel stroke, or a stroke of unknown cause had similar absolute rates for a first major coronary event and for any CHD event; transient ischemic attack, small vessel, and unknown cause groups had lower absolute revascularization procedure rates. Major coronary event, any CHD event, and any revascularization procedure rates were similarly reduced in all baseline stroke subtypes in the atorvastatin arm compared with placebo with no heterogeneity between groups. Conclusion— CHD risk can be substantially reduced by atorvastatin therapy in patients with recent stroke or transient ischemic attack regardless of stroke subtype.

Background and Purpose— The relative contributions of on-treatment low- and high-density lipoprotein cholesterol (LDL-C, HDL-C), triglycerides, and blood pressure (BP) control on the risk of recurrent stroke or major cardiovascular events in patients with stroke is not well defined. Methods— We randomized 4731 patients with recent stroke or transient ischemic attack and no known coronary heart disease to atorvastatin 80 mg per day or placebo. Results— After 4.9 years, at each level of LDL-C reduction, subjects with HDL-C value above the median or systolic BP below the median had greater reductions in stroke and major cardiovascular events and those with a reduction in triglycerides above the median or diastolic BP below the median showed similar trends. There were no statistical interactions between on-treatment LDL-C, HDL-C, triglycerides, and BP values. In a further exploratory analysis, optimal control was defined as LDL-C 50 mg per deciliter, triglycerides Conclusions— We found a cumulative effect of achieving optimal levels of LDL-C, HDL-C, triglycerides, and BP on the risk of recurrent stroke and major cardiovascular events. The protective effect of having a higher HDL-C was maintained at low levels of LDL-C.

Background and Purpose— The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial found that treatment with atorvastatin 80 mg per day reduced the risk of stroke and cardiovascular events in patients with a recent transient ischemic attack (TIA) or stroke. We hypothesized this benefit would be greatest in the subgroup of patients with carotid stenosis. Methods— The SPARCL trial randomized patients with TIA or stroke within 1 to 6 months without known coronary heart disease (CHD) and low-density lipoprotein cholesterol 100 to 190 mg/dL to treatment with atorvastatin 80 mg per day or placebo. Investigators identified subjects as having carotid stenosis not requiring revascularization at the time of randomization. Of the total SPARCL population, 1007 were documented as having carotid stenosis at baseline, 3271 did not, and the status of 453 was unknown. Results— We found no heterogeneity in the treatment effect for the SPARCL primary (fatal and nonfatal stroke) and secondary end points between the group with and without carotid stenosis. The group with carotid artery stenosis had greater benefit when all cerebro- and cardiovascular events were combined. In the group with carotid artery stenosis, treatment with atorvastatin was associated with a 33% reduction in the risk of any stroke (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.47, 0.94; P =0.02), and a 43% reduction in risk of major coronary events (HR 0.57, 95% CI 0.32, 1.00; P =0.05). Later carotid revascularization was reduced by 56% (HR 0.44, 95% CI 0.24, 0.79; P =0.006) in the group randomized to atorvastatin. Conclusion— Consistent with the overall results of the SPARCL intention to treat population, intense lipid lowering with atorvastatin reduced the risk of cerebro- and cardiovascular events in patients with and without carotid stenosis. The carotid stenosis group may have greater benefit.

Why Calls for More Routine Carotid Stenting Are Currently Inappropriate An International, Multispecialty, Expert Review and Position Statement

Background and Purpose Echolucent carotid atherosclerotic plaques are associated with an increased risk of neurological symptoms. Elevated plasma triglycerides is a risk factor for cerebral and coronary infarction. This study examined these individual pathogenetic risk factors to determine whether they were related. Methods We included 85 symptomatic patients with at least 40% carotid artery stenosis. Plaque morphology of the relevant artery was evaluated by high-resolution B-mode ultrasonography as echolucent, echo-rich, or intermediate. Fasting and postprandial lipids and lipoproteins were measured before and at hourly intervals for 4 hours after a fatty meal (1 g cream fat per kilogram body weight). Results When we compared patients with echolucent plaques to patients with echo-rich or intermediate plaques, the former had higher fasting and postprandial plasma triglycerides ( P ≤.006), higher chylomicron remnants/VLDL cholesterol ( P =.02) and triglycerides ( P ≤.004), a larger area under the plasma triglyceride curve 0 to 4 hours after a fatty meal, with (AUC TG−TG 0h ) or without (AUC TG ) subtraction of fasting levels ( P =.007 and P =.003), a larger body mass index ( P =.03), and were younger ( P =.01). Multiple logistic regression analysis found that when age and body mass index were taken into account, fasting plasma and VLDL triglycerides, postprandial chylomicron remnants/VLDL triglycerides, AUC TG−TG 0h and AUC TG with odds ratios of 4.1, 3.8, 3.0, 2.7, and 4.3, respectively, were independent predictors of an echolucent plaque. Conclusions Echolucent carotid artery plaques are associated with elevated levels of triglyceride-rich lipoproteins in the fasting or postprandial state.

Background and Purpose— Laboratory experiments suggest statins reduce stroke severity and improve outcomes. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial was a placebo-controlled, randomized trial designed to determine whether treatment with atorvastatin reduces strokes in subjects with recent stroke or transient ischemic attack (n=4731). We analyzed SPARCL trial data to determine whether treatment favorably shifts the distribution of severities of ischemic cerebrovascular outcomes. Methods— Severity was assessed with the National Institutes of Health Stroke Scale, Barthel Index, and modified Rankin Scale score at enrollment (1 to 6 months after the index event) and 90 days poststroke in subjects having a stroke during the trial. Results— Over 4.9 years, strokes occurred in 576 subjects. There were reductions in fatal, severe (modified Rankin Scale score 5 or 4), moderate (modified Rankin Scale score 3 or 2), and mild (modified Rankin Scale score 1 or 0) outcome ischemic strokes and transient ischemic attacks and an increase in the proportion of event-free subjects randomized to atorvastatin ( P P P =0.174 unadjusted, P =0.218 adjusted). If the analysis is restricted to those having an outcome ischemic stroke (ie, excluding those having a transient ischemic attack or no event), there was only a trend toward lesser severity with treatment based on the modified Rankin Scale score ( P =0.0647) with no difference based on the National Institutes of Health Stroke Scale or Barthel Index. Conclusion— The present exploratory analysis suggests that the outcome of recurrent ischemic cerebrovascular events might be improved among statin users as compared with nonusers.

Background and Purpose— The SPARCL trial showed that atorvastatin 80 mg/d reduces the risk of stroke and other cardiovascular events in patients with recent stroke or transient ischemic attack (TIA). We tested the hypothesis that the benefit of treatment varies according to index event stroke subtype. Methods— Subjects with stroke or TIA without known coronary heart disease were randomized to atorvastatin 80 mg/d or placebo. The SPARCL primary end point was fatal or nonfatal stroke. Secondary end points included major cardiovascular events (MCVE; stroke plus major coronary events). Cox regression models testing for an interaction with treatment assignment were used to explore potential differences in efficacy based on stroke subtype. Results— For subjects randomized to atorvastatin versus placebo, a primary end point occurred in 13.1% versus 18.6% of those classified as having large vessel disease (LVD, 15.8% of 4,731 participants), in 13.1% versus 15.5% of those with small vessel disease (SVD, 29.8%), in 11.2% versus 12.7% of those with ischemic stroke of unknown cause (21.5%), in 7.6% versus 8.8% of those with TIA (30.9%), and in 22.2% versus 8.3% of those with hemorrhagic stroke (HS, 2%) at baseline. There was no difference in the efficacy of treatment for either the primary end point (LVD hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.49 to 1.02, TIA HR 0.81, CI 0.57 to 1.17, SVD HR 0.85, CI 0.64 to 1.12, unknown cause HR 0.87, CI 0.61 to 1.24, HS HR 3.24, CI 1.01 to 10.4; P for heterogeneity=0.421), or MCVEs ( P for heterogeneity=0.360) based on subtype of the index event. As compared to subjects with LVD strokes, those with SVD had similar MCVE rates (19.2% versus 18.5% over the course of the trial), and similar overall reductions in stroke and MCVEs. Conclusions— Atorvastatin 80 mg/d is similarly efficacious in preventing strokes and other cardiovascular events, irrespective of baseline ischemic stroke subtype.

Background and Purpose— The intention-to-treat analysis of data from the placebo-controlled Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial found 80 mg atorvastatin per day reduced the risk of stroke and major coronary events in patients with recent stroke or transient ischemic attack. This benefit was present despite only a 78% net difference in adherence to randomized treatment over the course of the trial. In this exploratory analysis, our aim was to evaluate the benefit and risks associated with achieving a ≥50% low-density lipoprotein cholesterol (LDL-C) reduction from baseline. Methods— This post hoc analysis was based on 55 045 LDL-C measurements among the 4731 patients enrolled in SPARCL (average, 11.6 measurements per patient) during a mean follow-up of 4.9 years. At each postrandomization LDL-C assessment, percent change in LDL-C from baseline for each patient was classified as no change or increase from baseline (32.7% of measurements), Results— Compared with no change or an increase in LDL-C, analysis of time-varying LDL-C change showed that patients with ≥50% LDL-C reduction had a 31% reduction in stroke risk (hazard ratio, 0.69, 95% CI, 0.55 to 0.87, P =0.0016), a 33% reduction in ischemic stroke ( P =0.0018), no statistically significant increase in hemorrhagic stroke ( P =0.8864), and a 37% reduction in major coronary events ( P =0.0323). There was no increase in the incidence of myalgia or rhabdomyolysis. Persistent liver enzyme elevations were more frequent in the group with ≥50% LDL-C reduction. Conclusions— As compared with having no change or an increase in LDL-C, achieving a ≥50% lowering was associated with a greater reduction in the risk of stroke and major coronary events with no increase in brain hemorrhages.

To evaluate the accuracy of a pulsed multigated Doppler system, 128 carotid arteries were examined. The spectral broadening index was calculated from the power spectrum of a small sample volume located in the center of the stream according to the flow profile and was related to the degree of stenosis as determined by contrast angiography. Even minor wall irregularities seen on the angiogram were classified as disease. The ability of the system to discriminate between normal and diseased vessels reached a sensitivity of 94% and a specificity of 91%. Classification of greater than 50% or less than 50% stenosis could be performed with a sensitivity of 90% and a specificity of 85%. Pulsed multigated Doppler ultrasonography allows identification of even minor degrees of stenosis of the carotid artery and provides an alternative to duplex scanning. Furthermore, the blood flow profile provided by a multigated Doppler system may add valuable information concerning blood flow characteristics not obtainable by single-gated systems.

Cerebral blood flow was measured by the intravenous xenon-133 technique at rest and during cerebral vasodilation with acetazolamide in 32 patients before and after uncomplicated carotid endarterectomy. The results were compared with the internal carotid artery perfusion pressure measured during surgery. A significant improvement in side-to-side cerebral blood flow asymmetry occurred in 6 patients studied at baseline and in 11 patients during provoked cerebral vasodilation. These patients all belonged to a group of 14 patients who, in addition to a severe stenosis of the internal carotid artery, presented a reduction in cerebral perfusion pressure of at least 20%. No improvements occurred in 18 patients with no or only minor reduction in perfusion pressure, irrespective of the degree of stenosis. These findings indicate an improved perfusion reserve following carotid endarterectomy in most patients with marked reduction in perfusion pressure, whereas only some of these patients will experience an improvement in baseline cerebral blood flow.