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Background and Purpose— The insulin sensitizer, pioglitazone, reduces cardiovascular risk in patients after an ischemic stroke or transient ischemic attack but increases bone fracture risk. We conducted a secondary analysis of the IRIS trial (Insulin Resistance Intervention After Stroke) to assess the effect of pretreatment risk for fracture on the net benefits of pioglitazone therapy. Methods— IRIS was a randomized placebo-controlled trial of pioglitazone that enrolled patients with insulin resistance but without diabetes mellitus within 180 days of an ischemic stroke or transient ischemic attack. Participants were recruited at 179 international centers from February 2005 to January 2013 and followed for a median of 4.8 years. Fracture risk models were developed from patient characteristics at entry. Within fracture risk strata, we quantified the effects of pioglitazone compared with placebo by estimating the relative risks and absolute 5-year risk differences for fracture and stroke or myocardial infarction. Results— The fracture risk model included points for age, race-ethnicity, sex, body mass index, disability, and medications. The relative increment in fracture risk with pioglitazone was similar in the lower ( Conclusions— A simple point score identifying patients at low risk for fracture may assist in selecting patients with a favorable benefit-risk profile for pioglitazone therapy after ischemic stroke or transient ischemic attack.

Background and Purpose— The proportion of patients with acute ischemic stroke or transient ischemic attack (TIA) and obesity who successfully achieve goals for weight reduction recommended by major professional organizations is unknown. Methods— We examined the experience of participants in the placebo group of the IRIS trial (Insulin Resistance Intervention after Stroke) with a body mass index ≥30 kg/m 2 at entry. Patients were of age ≥40 years, with a qualifying stroke or TIA within 180 days of randomization and documented insulin resistance without diabetes mellitus. Weights at baseline and at years 1 and 2 after entry were analyzed to determine the proportion of patients achieving a 5% weight loss and achievement of body mass index 2 . Results— Of 1937 subjects assigned to placebo, 855 (44%) had obesity at entry. Median age of these 855 subjects was 60 years (interquartile range, 53–68), 41% were women, and median time from stroke/TIA to trial entry was 79 days. Among 788 subjects in the trial at 1 year, 166 (21%) had lost at least 5% of their starting weight and 12 (2%) had achieved a body mass index 2 . One hundred nine (14%) participants gained at least 5% of their baseline weight at 1 year. Among 744 subjects in the trial at 2 years, 185 (25%) had lost at least 5% of their baseline weight and 23 (3%) had achieved a body mass index 2 . One hundred forty (19%) participants gained at least 5% of their starting weight at 2 years. Conclusions— Only one quarter of obese patients with a recent ischemic stroke or TIA lost a clinically significant amount of weight after their vascular event. Many patients gained weight. Enhancing weight loss after ischemic stroke or TIA may help improve functional outcome and reduce risk for future vascular events, but clinical trials are needed to test and confirm these potential benefits.

Objective: Standards for reporting and analyzing adherence to medical therapy have recently improved due to international consensus efforts. We report adherence in a stroke trial using the EMERGE guidelines and demonstrate how support of patients can lead to adherence recovery during therapy implementation. Methods: We analyzed 3 phases of adherence according to current taxonomy in the Insulin Resistance Intervention after Stroke (IRIS) trial: initiation (did patient start drug), implementation (did patient take a drug holiday, defined as temporary cessation lasting ≥14 days), and persistence (did patient permanently and prematurely discontinue drug). IRIS was a randomized, placebo controlled trial testing pioglitazone to prevent stroke or MI in patients with ischemic stroke/TIA and insulin resistance. Adherence was classified by self-report. Researchers used coaching algorithms to seek adherence recovery if participants went off drug. Results: During 2005-2013, 3876 participants were enrolled from 179 sites in 7 countries. Mean age was 63.5 years; 65% were male, 11% Black race, and 4% Hispanic ethnicity. A total of 26 patients ( Conclusion: For the first time in a stroke trial, we report adherence according to internationally recommended guidelines. Results show that holidays are common, but participants will resume drug with coaching. Among reasons for drug cessation, only those secondary to study protocol were unavoidable and misattributions of AEs to study drug were common as seen in the placebo group. Our findings have implications for trials that require high drug adherence to successfully answer scientific hypotheses.

Pioglitazone reduces insulin resistance and cardiovascular risk among patients with type 2 diabetes. The Insulin Resistance Intervention after Stroke (IRIS) trial randomized 3876 non-diabetic participants with recent stroke/TIA and insulin resistance based on the Homeostasis Model of Insulin Resistance (HOMA-IR) score to pioglitazone (PIO) vs. placebo (PLA). Over 4.8 years, the relative risk reduction (RRR) with PIO was 27% for stroke/myocardial infarction, 25% for stroke, 29% for acute coronary syndrome (ACS), and 52% for new-onset diabetes. PIO could therefore be considered a new therapy for secondary stroke prevention before diabetes onset. However, it is not in widespread use, not only because of increased fracture risk, but perhaps also because HOMA-IR is not commonly assessed in clinical practice. In contrast, the presence of prediabetes is often identified in this population. We therefore analyzed the intention-to-treat (ITT) and the on-treatment effect of PIO (defined as adherence of > 80%) in IRIS participants with prediabetes by the American Diabetes Association criteria: HbA1C 5.7%-6.4%, or fasting glucose 100-125 mg/dL (n=2885; PIO 1456, PLA 1429). By ITT, for pioglitazone the hazard ratio and 95% confidence interval in Cox regression for stroke/MI was 0.70 (0.56-0.88, p=0.002), for stroke 0.72 (0.56-0.93, p=0.013), for ACS 0.72 (0.52-1.00, p = 0.052), for stroke/MI/hospitalized heart failure (HHF) 0.78 (0.63-0.96, p=0.02), and for new-onset diabetes HR 0.46 (0.34-0.61, p Conclusion: Pioglitazone should be considered efficacious for secondary prevention in stroke/TIA participants with prediabetes, simply assessed by fasting plasma glucose or A1C.

Background: The Insulin Resistance Intervention after Stroke (IRIS) trial demonstrated that pioglitazone reduced risk for the composite outcome of stroke or myocardial infarction among non-diabetic patients with insulin resistance and a recent ischemic stroke or TIA. The drug also reduced risk for stroke alone, but the finding did not reach statistical significance. During the trial, the Data & Safety Monitoring Board approved a secondary analysis using updated 2013 consensus criteria for ischemic stroke. Our objective is to examine the effect of pioglitazone, compared with placebo, on risk for stroke alone defined by the 2013 criteria. Methods: Participants were randomized to pioglitazone (45 mg per day target dose) or placebo and followed for a maximum of 5 years. An independent committee, blinded to treatment assignments, adjudicated all potential stroke outcomes. The primary outcome was any stroke, but we also examined type of stroke (ischemic or hemorrhagic), and ischemic stroke subtype. Results: Among 3876 IRIS participants (mean age 63 years, 65% male), 377 stroke events were observed in 319 participants over a median follow-up of 4.8 years (329 stroke events by the original trial criteria plus 48 new events identified by applying the 2013 stroke criteria). Pioglitazone was associated with a 25% risk reduction for any stroke (8.0% compared to 10.7%; hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.60 to 0.94) and a 28% reduction for ischemic stroke (HR, 0.72; 95% CI, 0.57 to 0.9) but not hemorrhagic stroke (HR, 1.00; 95% CI, 0.50-2.00). Pioglitazone was associated with fewer numbers of all subtypes of ischemic stroke, but the difference from placebo reached or approached significance only for lacunar (HR, 0·46; 95% CI, 0·22-0·93; p=0·03) and large vessel (HR, 0·59; 95% CI, 0·33-1·04; p=0·07) strokes. Conclusion: Pioglitazone prevents recurrent ischemic stroke among non-diabetic patients with insulin resistance.

Background and Purpose— Transient ischemic attack (TIA) patients are at risk of recurrent vascular events. The primary objectives were to evaluate among TIA patients the prevalence of sleep apnea and among patients with sleep apnea auto-titrating continuous positive airway pressure (auto-CPAP) adherence. The secondary objective was to describe among TIA patients with sleep apnea the recurrent vascular event rate by auto-CPAP use category. Methods— All intervention patients received auto-CPAP for 2 nights, but only intervention patients with evidence of sleep apnea received auto-CPAP for the remainder of the 90-day period. Intervention patients received polysomnography at 90 days after TIA. Control patients received polysomnography at baseline and at 90 days. Acceptable auto-CPAP adherence was defined as ≥4 hours per night for ≥75% of nights. Vascular events included recurrent TIA, stroke, hospitalization for congestive heart failure, myocardial infarction, or death. Results— We enrolled 70 acute TIA patients: 45 intervention and 25 control. The majority of patients had sleep apnea: 57% at baseline and 59% at 90 days. Among the 30 intervention patients with airflow obstruction, 12 (40%) had acceptable auto-CPAP adherence, 18 (60%) had some use, and none had no use. Three intervention patients (12%) had recurrent events compared with 1 (2%; P =0.13) control patient. The vascular event rate was highest among sleep apnea patients with no CPAP use: none, 16%; some, 5%; acceptable adherence 0% ( P =0.08). Conclusions— Sleep apnea is common among acute TIA patients. It appears feasible to provide auto-CPAP in the acute TIA period. Larger studies should evaluate whether a strategy of diagnosing and treating sleep apnea can reduce recurrent vascular events after TIA.

Background —Time is of the essence for effective intervention in acute ischemic stroke. Efforts including stroke teams that are “on call” around-the-clock are emerging to reduce the time from emergency room arrival to evaluation and treatment. Summary of Comment —Based on the results of the NINDS rt-PA Stroke Trial, which demonstrated both clinical effectiveness in reducing neurological deficits and disability and cost savings to health care systems, many community hospitals and managed-care organizations are exploring methods to enhance and expedite acute stroke care in their local communities. Only a small fraction of acute stroke victims is currently treated with thrombolytics ( Conclusions —Computer-based technology can now be used to integrate electronic medical information, clinical assessment tools, neuroradiology, laboratory data, and clinical pathways to bring state-of-the-art expert stroke care to underserved areas.

Background and Purpose —Intravenous tissue plasminogen activator (tPA) administered within 3 hours of symptom onset is the first available effective therapy for acute ischemic stroke (AIS). Few data exist, however, on its use in very elderly patients. We examined the characteristics, complications, and short-term outcome of AIS patients aged ≥80 years treated with tPA. Methods —Patients aged ≥80 years (n=30) were compared with counterparts aged Results —Risk of intracerebral hemorrhage (fatal, symptomatic, and total) was 3%, 3%, and 7% in the elderly age group and 2%, 6%, and 9%, respectively, in their younger counterparts ( P =NS for all comparisons). Likelihood of favorable outcome, defined as modified Rankin score 0 to 1, National Institutes of Health Stroke Scale score ≤5, or marked improvement by hospital discharge, was comparable between groups (37%, 54%, and 43% versus 30%, 54%, and 43%, respectively; P =NS for all comparisons). Elderly patients were more likely to be treated by stroke specialists (87% versus 60%; P =0.005) and less likely to have an identified protocol deviation (13% versus 33%; P =0.03). Elderly patients were discharged more often to nursing care facilities (17% versus 5%; P =0.003). In logistic regression models there were no differences in odds ratio for favorable or poor outcome, other than tendency for higher in-hospital mortality in elderly patients (odds ratio, 2.8; 95% CI, 0.81 to 9.62; P =0.10). Conclusions —Among AIS patients treated with intravenous tPA, age-related differences in characteristics and disposition were identified. No evidence for withholding tPA treatment for AIS in appropriately selected patients aged ≥80 years was identified.

Background and Purpose —Ataxic hemiparesis is a well-recognized lacunar syndrome involving homolateral ataxia with accompanying corticospinal tract impairment. Despite 30 years of clinical experience there continues to be some doubt as to the defining clinical characteristics, precise neuroanatomic localization of the syndrome, and etiologic mechanisms. Methods —We now present 45 new cases that have been analyzed for clinico-radiologic correlation and etiology. Also, all published cases from the English literature known to the authors are reviewed. Results —We found that the clinical syndrome of ataxic hemiparesis accurately predicts a small deep infarction, generally in the pons or internal capsule. Sensory loss is highly associated with a capsular localization. We found that 47% of the cases were attributed to small-vessel disease, 11% to cardioembolism, and only 7% to artery-to-artery embolism (all in the basilar artery); 1 case was attributed to thrombocytosis, 1 to multiple sclerosis, and the rest either had negative or incomplete evaluation. Approximately two thirds of the infarctions occurred in patients with neuroimaging evidence of other ischemic brain lesions. Conclusions —Ataxic hemiparesis is a distinct clinical syndrome that accurately predicts a small deep infarction, most commonly in the pons or internal capsule. Only sensory loss accurately predicts a capsular localization. Etiology in nearly half of the cases can be attributed to small-vessel disease. Furthermore, ataxic hemiparesis appears to be a good marker for generalized asymptomatic cerebrovascular disease.