Background Recurrent vascular events remain a major source of morbidity and mortality after stroke or transient ischemic attack (TIA). The IRIS Trial is evaluating an approach to secondary prevention ...based on the established association between insulin resistance and increased risk for ischemic vascular events. Specifically, IRIS will test the effectiveness of pioglitazone, an insulin-sensitizing drug of the thiazolidinedione class, for reducing the risk for stroke and myocardial infarction (MI) among insulin resistant, nondiabetic patients with a recent ischemic stroke or TIA. Design Eligible patients for IRIS must have had insulin resistance defined by a Homeostasis Model Assessment–Insulin Resistance >3.0 without meeting criteria for diabetes. Within 6 months of the index stroke or TIA, patients were randomly assigned to pioglitazone (titrated from 15 to 45 mg/d) or matching placebo and followed for up to 5 years. The primary outcome is time to stroke or MI. Secondary outcomes include time to stroke alone, acute coronary syndrome, diabetes, cognitive decline, and all-cause mortality. Enrollment of 3,876 participants from 179 sites in 7 countries was completed in January 2013. Participant follow-up will continue until July 2015. Summary The IRIS Trial will determine whether treatment with pioglitazone improves cardiovascular outcomes of nondiabetic, insulin-resistant patients with stroke or TIA. Results are expected in early 2016.
Background White matter hyperintensity (WMH), a common radiographic finding associated with stroke risk and outcome, has been linked to matrix metalloproteinase (MMP) activity and increased levels of ...oxidative stress in nonstroke populations. We sought to determine whether WMH severity is associated with plasma levels of MMPs and oxidative stress (F2-isoprostane) in subjects with acute ischemic stroke (AIS). Methods We measured plasma biomarker levels at baseline and 48 hours in consecutive AIS subjects. White matter hyperintensity volume (WMHv) was quantified on admission magnetic resonance imaging using a validated semiautomated protocol, and Spearman correlation coefficients were derived for all measured biomarkers. Results We enrolled 405 AIS subjects (mean age 70 ± 15 years; 58% male; median WMHv 3.4 cm3 , interquartile range 1.4-9.5). WMHv and age were strongly correlated (ρ = .57, P < .0001). WMHv and MMP-2 levels were correlated at baseline (ρ = .23, P < .0001) and at 48 hours poststroke (ρ = .19, P = .002). In multivariate analysis, 48-hour MMP-2 levels were independently associated with WMHv (β = .12, P = .04). MMP-9 and F2-isioprostane levels did not correlate with WMHv. Conclusions In AIS patients, MMP-2 levels are associated with the pre-existing burden of WMH. If validated, these findings may further elucidate the role of MMP-2 in pathophysiology of chronic cerebrovascular injury, such as WMH, and in brain susceptibility to acute ischemia.
Goal We sought to develop an instrument to screen for insulin resistance in nondiabetic patients with recent ischemic stroke or transient ischemic attack (TIA). Materials and methods Subjects were ...7262 nondiabetic patients aged greater than or equal to 40 years with ischemic strokes or TIA within the past 6 months. Features were analyzed in bivariate analysis for association with insulin resistance, measured by the homeostasis model assessment of insulin resistance (HOMA-IR). Features significantly associated with HOMA-IR ( P < .05) were entered into multivariable analysis. The magnitudes of regression coefficients from the multivariable model were used to assign point values for 2 diagnostic scoring instruments: a basic instrument and an enhanced instrument incorporating and not incorporating laboratory values, respectively. The performance of the instruments was tested using receiver operating characteristic (ROC) analysis. Findings In the basic model, 5 features were retained in the multivariable regression analysis: male gender, abdominal obesity, body mass index (BMI), elevated waist-to-hip ratio, and systolic blood pressure. In the enhanced model, 4 features were retained in the multivariable regression analysis: BMI, abdominal obesity, fasting glucose greater than or equal to 100 mg/dL, and triglyceride/high-density lipoprotein ratio. In the basic model, the area under the ROC curve (aROC) was .73 in the validation cohort. In the enhanced model, the aROC was .78 in the validation cohort. Conclusions Our 2 scoring systems performed well in identifying stroke patients with insulin resistance, but they are probably not sufficiently accurate for high-stake clinical decisions. We suggest strategies for improving the accuracy of future instruments.
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