Partial Meal Replacement for Weight Loss after Stroke: Results of a Pilot Clinical Trial.

INTRODUCTION: Over half of patients with acute ischemic stroke are overweight or obese as defined by a body mass index (BMI) ≥25 kg/m2. Professional and government agencies recommend weight management for these persons to improve risk factors for cardiovascular disease, including hypertension, dyslipidemia, vascular inflammation, and diabetes. However, approaches to weight loss have not been adequately tested specifically in patients with stroke. In anticipation of a larger trial with vascular or functional outcomes, we tested the feasibility and safety of a 12-week partial meal replacement (PMR) intervention for weight loss in overweight or obese patients with a recent ischemic stroke. METHODS: This randomized open-label trial enrolled participants from December 2019 to February 2021 (with hiatus from March to August 2020 due to COVID-19 pandemic restrictions on research). Eligible patients had a recent ischemic stroke and BMI 27-49.9 kg/m2. Patients were randomized to a PMR diet (OPTAVIA® Optimal Weight 4 & 2 & 1 Plan®) plus standard care (SC) or SC alone. The PMR diet consisted of four meal replacements supplied to participants, two meals with lean protein and vegetables (self-prepared or supplied), and a healthy snack (also self-prepared or supplied). The PMR diet provided 1,100-1,300 calories per day. SC consisted of one instructional session on a healthy diet. Co-primary outcomes were ≥5% weight loss at 12 weeks and to identify barriers to successful weight loss among participants assigned to PMR. Safety outcomes included hospitalization, falls, pneumonia, or hypoglycemia requiring treatment by self or others. Due to the COVID-19 pandemic, study visits after August 2020 were by remote communication. RESULTS: We enrolled 38 patients from two institutions. Two patients in each arm were lost and could not be included in outcome analyses. At 12 weeks, 9/17 patients in the PMR group and 2/17 patients in the SC group achieved ≥5% weight loss (52.9% vs. 11.9%; Fisher's exact p = 0.03). Mean percent weight change in the PMR group was -3.0% (SD 13.7) and -2.6% (SD 3.4) in the SC group (Wilcoxon rank-sum p = 0.17). No adverse events were attributed to study participation. Some participants had difficulty completing home monitoring of weight. In the PMR group, participants reported that food cravings and dislike for some food products were barriers to weight loss. CONCLUSION: A PMR diet after ischemic stroke is feasible, safe, and effective for weight loss. In future trials, in-person or improved remote outcome monitoring may reduce anthropometric data variation.

Effects of oral anticoagulation in people with atrial fibrillation after spontaneous intracranial haemorrhage (COCROACH): prospective, individual participant data meta-analysis of randomised trials.

BACKGROUND: The safety and efficacy of oral anticoagulation for prevention of major adverse cardiovascular events in people with atrial fibrillation and spontaneous intracranial haemorrhage are uncertain. We planned to estimate the effects of starting versus avoiding oral anticoagulation in people with spontaneous intracranial haemorrhage and atrial fibrillation. METHODS: In this prospective meta-analysis, we searched bibliographic databases and trial registries using the strategies of a Cochrane systematic review (CD012144) on June 23, 2023. We included clinical trials if they were registered, randomised, and included participants with spontaneous intracranial haemorrhage and atrial fibrillation who were assigned to either start long-term use of any oral anticoagulant agent or avoid oral anticoagulation (ie, placebo, open control, another antithrombotic agent, or another intervention for the prevention of major adverse cardiovascular events). We assessed eligible trials using the Cochrane Risk of Bias tool. We sought data for individual participants who had not opted out of data sharing from chief investigators of completed trials, pending completion of ongoing trials in 2028. The primary outcome was any stroke or cardiovascular death. We used individual participant data to construct a Cox regression model of the time to the first occurrence of outcome events during follow-up in the intention-to-treat dataset supplied by each trial, followed by meta-analysis using a fixed-effect inverse-variance model to generate a pooled estimate of the hazard ratio (HR) with 95% CI. This study is registered with PROSPERO, CRD42021246133. FINDINGS: We identified four eligible trials; three were restricted to participants with atrial fibrillation and intracranial haemorrhage (SoSTART [NCT03153150], with 203 participants) or intracerebral haemorrhage (APACHE-AF [NCT02565693], with 101 participants, and NASPAF-ICH [NCT02998905], with 30 participants), and one included a subgroup of participants with previous intracranial haemorrhage (ELDERCARE-AF [NCT02801669], with 80 participants). After excluding two participants who opted out of data sharing, we included 412 participants (310 [75%] aged 75 years or older, 249 [60%] with CHA2DS2-VASc score ≤4, and 163 [40%] with CHA2DS2-VASc score >4). The intervention was a direct oral anticoagulant in 209 (99%) of 212 participants who were assigned to start oral anticoagulation, and the comparator was antiplatelet monotherapy in 67 (33%) of 200 participants assigned to avoid oral anticoagulation. The primary outcome of any stroke or cardiovascular death occurred in 29 (14%) of 212 participants who started oral anticoagulation versus 43 (22%) of 200 who avoided oral anticoagulation (pooled HR 0·68 [95% CI 0·42-1·10]; I2=0%). Oral anticoagulation reduced the risk of ischaemic major adverse cardiovascular events (nine [4%] of 212 vs 38 [19%] of 200; pooled HR 0·27 [95% CI 0·13-0·56]; I2=0%). There was no significant increase in haemorrhagic major adverse cardiovascular events (15 [7%] of 212 vs nine [5%] of 200; pooled HR 1·80 [95% CI 0·77-4·21]; I2=0%), death from any cause (38 [18%] of 212 vs 29 [15%] of 200; 1·29 [0·78-2·11]; I2=50%), or death or dependence after 1 year (78 [53%] of 147 vs 74 [51%] of 145; pooled odds ratio 1·12 [95% CI 0·70-1·79]; I2=0%). INTERPRETATION: For people with atrial fibrillation and intracranial haemorrhage, oral anticoagulation had uncertain effects on the risk of any stroke or cardiovascular death (both overall and in subgroups), haemorrhagic major adverse cardiovascular events, and functional outcome. Oral anticoagulation reduced the risk of ischaemic major adverse cardiovascular events, which can inform clinical practice. These findings should encourage recruitment to, and completion of, ongoing trials. FUNDING: British Heart Foundation.

Separate But Not Equal? A Cross-Sectional Study of Segregation by Payor Mix in Academic Primary Care Clinics.

BACKGROUND: At some US Academic Health Centers (AHCs), patients with predominantly Medicaid insurance are seen in one clinic and patients with other insurance are seen in another. The extent of this practice and implications are unknown. OBJECTIVE: To estimate the proportion of AHCs that have at least two primary care internal medicine clinics that differ substantially in proportion of patients with Medicaid and to compare patient demographic, staffing, and operational features. PARTICIPANTS: General internal medicine chiefs and clinic directors at 40 randomly selected US AHCs plus the top 10 AHCs in terms of NIH funding. MAIN MEASURE: An AHC was classified as maintaining clinics that differed substantially in the proportion of patients with Medicaid if any two differed by ≥ 40% (absolute). Other criteria were used for pre-specified secondary analyses (e.g., ≥ 30%). KEY RESULTS: Thirty-nine of 50 AHCs (78%) participated. Four of 39 (10%; 95% CI, 3 to 24%) had two clinics differing by ≥ 40% in the proportion of patients with Medicaid, eight (21%; 95% CI, 9 to 36%) had clinics differing by ≥ 30%, and 15 (38%; 95% CI, 23 to 55%) had clinics differing by ≥ 20%. Clinics with more patients with Medicaid by any of the three criteria were more likely to employ resident physicians as providers of longitudinal care (with faculty supervision) and more likely to have patients who were Black or Hispanic. CONCLUSIONS: Some US AHCs maintain separate clinics defined by the proportion of patients with Medicaid. Clinics with a higher proportion of patients insured by Medicaid are more likely to employ residents (with faculty oversight), feature residents as providers of longitudinal care, and serve patients who are Black and Hispanic. Further research is needed to understand why some AHCs have primary care clinics distinguishable by insurance mix with the goal of ensuring that racism and discrimination are not root causes.

Technical Dissonance in Home Blood Pressure Monitoring After Stroke: Having the Machine, but Not Using Correctly.

BACKGROUND: In individuals with hypertension (HTN), lowering blood pressure (BP) after a stroke can lower the risk of stroke recurrence, but many patients do not reach the goal. Home blood pressure monitoring (HBPM) can help patients get to the goal, but rates of use and quality of technique have not been evaluated. METHODS: We conducted a cross-sectional study of patients with stroke. Patients were eligible if they had a stroke within 2 years, had HTN, and lived at home. We classified patients as correctly performing HBPM if they used an arm cuff, sat ≥ 1 min before measurement, took ≥ 2 measurements, and use within 6 months. The primary outcome was the proportion of patients who had an HBPM and used it correctly, which we calculated according to race and ethnicity. We also asked patients what they would do if they found results outside the goal. RESULTS: Among 150 participants, 120 (81%) possessed an HBPM and 29 (21%) used it correctly. We observed no significant disparity in rates of possession or correct use between non-Hispanic White participants and participants from underrepresented groups. Seventy percent of non-Hispanic White patients said they would contact their provider if their BP was above goal vs. 52% of underrepresented patients (P = 0.21). CONCLUSIONS: Most patients after stroke have an HBPM, but only about 1 in 5 use it correctly. Approximately half of the patients from underrepresented racial or ethnic groups do not have a plan for responding to the values above goal. Our results indicate opportunities to improve the dissemination and correct use of HBPM.

Central vs site outcome adjudication in the IRIS trial.

BACKGROUND: Central adjudication of outcome events is the standard in clinical trial research. We examine the benefit of central adjudication in the Insulin Resistance Intervention after Stroke (IRIS) trial and show how the benefit is influenced by outcome definition and features of the adjudicated events. METHODS: IRIS tested pioglitazone for prevention of stroke and myocardial infarction in patients with a recent transient ischemic attack or ischemic stroke. We compared the hazard ratios for study outcomes classified by site and central adjudication. We repeated the analysis for an updated stroke definition. RESULTS: The hazard ratios for the primary outcome were identical (0.76) and statistically significant regardless of adjudicator. The hazard ratios for stroke alone were nearly identical with site and central adjudication, but only reached significance with site adjudication (HR, 0.80; p = 0.049 vs. HR, 0.82; p = 0.09). Using the updated stroke definition, all hazard ratios were lower than with the original IRIS definition and statistically significant regardless of adjudication method. Agreement was higher when stroke type was certain, subtype was large vessel or cardioembolic, signs or symptoms lasted > 24 h, imaging showed a stroke, and when NIHSS was ≥3. DISCUSSION: Central stroke adjudication caused the hazard ratio for a main secondary outcome in IRIS (stroke alone) to be higher and lose statistical significant compared with site review. The estimate of treatment effects were larger with the updated stroke definition. There may be benefit of central adjudication for events with specific features, such as shorter symptom duration or normal brain imaging.

In Search of the Optimal Antithrombotic Regimen for Intracerebral Hemorrhage Survivors with Atrial Fibrillation.

Spontaneous intracerebral hemorrhage (ICH) constitutes 10-15% of all strokes, and is a significant cause of mortality and morbidity. Survivors of ICH, especially those with atrial fibrillation (AF), are at risk for both recurrent hemorrhagic and ischemic cerebrovascular events. A conundrum in the field of vascular neurology, neurosurgery, and cardiology has been the decision to initiate or resume versus withhold anticoagulation in survivors of ICH with AF. To initiate anticoagulation would decrease the risk of ischemic stroke but may increase the risk of hemorrhage. To withhold anticoagulation maintains a lower risk of hemorrhage but does not decrease the risk of ischemic stroke. In this narrative review, we discuss the evidence for and against the use of antithrombotics in ICH survivors with AF, focusing on recently completed and ongoing clinical trials.

Efficacy of lower doses of pioglitazone after stroke or transient ischaemic attack in patients with insulin resistance.

AIMS: Pioglitazone is a potent insulin-sensitizing drug with anti-atherosclerotic properties, but adverse effects have limited its use. We assessed the benefits and risks of lower versus higher doses of pioglitazone taken by participants in the Insulin Resistance Intervention in Stroke Trial. MATERIALS AND METHODS: Efficacy [myocardial infarction (MI) or recurrent stroke] new-onset diabetes) and adverse outcomes (oedema, weight gain, heart failure and bone fracture) were examined for subjects assigned to pioglitazone or placebo within strata defined by mode dose of study drug taken (i.e. the dose taken on most days in the study). RESULTS: Among the 1938 patients randomized to pioglitazone, the mode dose was <15 mg/day in 546 participants, 15 mg/day in 128, 30 mg/day in 89, and 45 mg/day in 1175. There was no significant effect on stroke/MI or new-onset diabetes with <15 mg/day. For 15 mg/30 mg/day pooled, the adjusted hazard ratios (95% CI) for stroke/MI were 0.48 (0.30, 0.76; p = .002) and 0.74 (0.69, 0.94) for 45 mg/day. For new-onset diabetes, the adjusted hazard ratios were 0.34 (0.15, 0.81; p = .001) and 0.31 (0.59, 0.94; p = .001) respectively. For oedema, weight gain and heart failure, the risk estimates for pioglitazone were lower for subjects taking <45 mg daily. For fractures, the increased risk with pioglitazone was similar across all dose strata. CONCLUSIONS: Lower doses of pioglitazone appear to confer much of the benefit with less adverse effects than the full dose. Further study is needed to confirm these findings so that clinicians may optimize dosing of this secondary prevention strategy in patients with stroke.

Adherence to study drug in a stroke prevention trial"?>.

OBJECTIVE: Standards for reporting and analyzing adherence to medical therapy have recently improved due to international consensus efforts. If applied to clinical trial research in patients with stroke, these improvements have the potential to identify when in the sequence of trial operations participants are at risk for non-adherence and opportunities to safeguard adherence. METHODS: We analyzed three phases of adherence according to the European Society for Patient Adherence, COMpliance, and Persistence (ESPACOMP) Medication Adherence Reporting Guideline (EMERGE) 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 prematurely and permanently discontinue drug). IRIS was a randomized, placebo controlled, double-blind trial testing pioglitazone to prevent stroke or myocardial infarction in patients with a recent ischemic stroke or transient ischemic attack. 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 seven countries and followed for a mean of 4.8 years. Less than 1% of participants in each group did not initiate study drug. 20% of patients assigned to pioglitazone and 17% assigned to placebo took at least one drug holiday. 36% and 30%, respectively, discontinued the study drug prematurely with or without a prior holiday. The risk for stopping the study drug (temporarily or permanently) in the first year after randomization was twice the risk in each of the subsequent four years. This was true both for patients assigned to active therapy and placebo. More participants assigned to pioglitazone, compared to placebo, took a drug holiday or permanently stopped study drug, but the difference in rates of discontinuation was only evident in year one. In years two through five, rates of discontinuation were similar in the two treatment groups. The difference in rates during year one was the result of adverse effects related to the active study drug, pioglitazone. During the remainder of the trial, the attribution of discontinuations to adverse effects potentially related to pioglitazone was reduced but still higher in those assigned to active drug. Other reasons for discontinuation were similar between treatment groups and were largely unrelated to pharmacodynamic effects of the study drug. Rates of discontinuation varied widely among research sites. CONCLUSION: Patients in a drug trial for stroke prevention are at greatest risk for premature drug discontinuation early after randomization. Reasons for discontinuation change over time. Variable discontinuation rates among sites suggests that adherence can be improved by using best practices from high-performing sites.

Achievement of Guideline-Recommended Weight Loss Among Patients With Ischemic Stroke and Obesity.

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/m2 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 <27 kg/m2. 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 <27 kg/m2. 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 <27 kg/m2. 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.

Pioglitazone Therapy in Patients With Stroke and Prediabetes: A Post Hoc Analysis of the IRIS Randomized Clinical Trial.

Importance: In the Insulin Resistance Intervention After Stroke (IRIS) randomized clinical trial, pioglitazone, an insulin-sensitizing agent, reduced the risk for recurrent stroke or myocardial infarction (MI) among patients with insulin resistance. However, insulin resistance is not commonly measured in clinical practice. Objective: To analyze the effects of pioglitazone in patients with good adherence as well as intention-to-treat effects of pioglitazone in patients with prediabetes in the IRIS trial. Design, Setting, and Participants: The IRIS trial was a randomized multicenter clinical trial in patients with prior stroke or transient ischemic attack as well as insulin resistance but not diabetes. Patients were enrolled from February 2005 to January 2013, and the median follow-up was 4.8 years. The post hoc analyses reported here were performed from June to September 2018. Per American Diabetes Association criteria, prediabetes was defined as having a hemoglobin A1c level of 5.7% to 6.4% or fasting plasma glucose level of 100 mg/dL to 125 mg/dL (to convert to mmol/L, multiply by 0.0555). Good adherence was defined as taking 80% or more of the protocol dose. Fasting glucose and hemoglobin A1c, used to define prediabetes, and adherence of 80% or higher, stipulated in the protocol as defining good adherence, were prespecified subgroups in the analysis plan. Interventions: Participants were randomized to 15 mg of pioglitazone, with dose titrated to target of 45 mg daily, or matching placebo. Main Outcomes and Measures: The primary outcome was recurrent stroke or MI. Secondary outcomes included stroke, acute coronary syndrome, stroke/MI/hospitalization for heart failure, and progression to diabetes. Results: Among 3876 participants analyzed in the IRIS trial, 2885 were included in this analysis (1456 in the pioglitazone cohort and 1429 in the placebo cohort). The mean (SD) age of patients was 64 (11) years, and 974 (66.9%) and 908 (63.5%) of patients were men in the pioglitazone and placebo cohort, respectively. In the prediabetic population with good adherence (644 of 1456 individuals [44.2%] in the pioglitazone group and 810 of 1429 [56.7%] in the placebo group), the hazard ratios (95% CI) were 0.57 (0.39-0.84) for stroke/MI, 0.64 (0.42-0.99) for stroke, 0.47 (0.26-0.85) for acute coronary syndrome, 0.61 (0.42-0.88) for stroke/MI/hospitalization for heart failure, and 0.18 (0.10-0.33) for progression to diabetes. There was a nonsignificant reduction in overall mortality, cancer, and hospitalization, a slight increase in serious bone fractures, and an increase in weight gain and edema. Intention-to-treat results also showed significant reduction of events but to a lesser degree. Hazard ratios (95% CI) were 0.70 (0.56-0.88) for stroke/MI, 0.72 (0.56-0.92) for stroke, 0.72 (0.52-1.00) for acute coronary syndrome, 0.78 (0.63-0.96), for stroke/MI/hospitalization for heart failure, and 0.46 (0.35 to 0.61) for progression to diabetes. Conclusions and Relevance: Pioglitazone may be effective for secondary prevention in patients with stroke/transient ischemic attack and with prediabetes, particularly in those with good adherence. Trial Registration: ClinicalTrials.gov identifier: NCT00091949.

Metabolic syndrome identifies normal weight insulin-resistant stroke patients at risk for recurrent vascular disease.

BACKGROUND: The obesity paradox refers to the finding in observational studies that patients with obesity have a better prognosis after stroke than normal weight patients. AIM: To test the hypothesis that there might be important heterogeneity within the obese stroke population, such that those with metabolic syndrome would be at higher risk for stroke or myocardial infarction and all-cause mortality compared to patients without metabolic syndrome. METHODS: The Insulin Resistance Intervention after Stroke trial enrolled non-diabetic patients with a recent ischemic stroke or transient ischemic attack and insulin resistance. We examined the association between metabolic syndrome and outcome risk in patients with normal weight at entry (body mass index (BMI) = 18.5-24.9 kg/m2), overweight (BMI = 25-29.9 kg/m2), or obesity (BMI ≥ 30 kg/m2). Analyses were adjusted for demographic features, treatment assignment, smoking, and major comorbid conditions. RESULTS: Metabolic syndrome was not associated with greater risk for stroke or myocardial infarction among 1536 patients who were overweight (adjusted hazard ratio (HR), 0.95; 95% confidence interval (CI): 0.69-1.31) or 1626 obese patients (adjusted HR, 1.00; 95% CI: 0.70-1.41). However, among 567 patients with a normal BMI, metabolic syndrome was associated with increased risk for stroke or myocardial infarction (adjusted HR, 2.05; 95% CI: 1.25-3.37), and all-cause mortality (adjusted HR, 1.70; 95% CI: 1.03-2.81) compared to patients without metabolic syndrome. CONCLUSIONS: The presence of metabolic syndrome identified normal weight patients with insulin resistance but no diabetes who have a higher risk of adverse cardiovascular outcomes, compared with patients without metabolic syndrome.

Scoring System to Optimize Pioglitazone Therapy After Stroke Based on Fracture Risk.

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 (

Heart Failure After Ischemic Stroke or Transient Ischemic Attack in Insulin-Resistant Patients Without Diabetes Mellitus Treated With Pioglitazone.

BACKGROUND: The IRIS trial (Insulin Resistance Intervention After Stroke) demonstrated that pioglitazone reduced the risk for both cardiovascular events and diabetes mellitus in insulin-resistant patients. However, concern remains that pioglitazone may increase the risk for heart failure (HF) in susceptible individuals. METHODS: In IRIS, patients with insulin resistance but without diabetes mellitus were randomized to pioglitazone or placebo (1:1) within 180 days of an ischemic stroke or transient ischemic attack and followed for ≤5 years. To identify patients at higher HF risk with pioglitazone, we performed a secondary analysis of IRIS participants without HF history at entry. HF episodes were adjudicated by an external review, and treatment effects were analyzed using time-to-event methods. A baseline HF risk score was constructed from a Cox model estimated using stepwise selection. Baseline patient features (individually and summarized in risk score) and postrandomization events were examined as possible modifiers of the effect of pioglitazone. Net cardiovascular benefit was estimated for the composite of stroke, myocardial infarction, and hospitalized HF. RESULTS: Among 3851 patients, the mean age was 63 years, and 65% were male. The 5-year HF risk did not differ by treatment (4.1% pioglitazone, 4.2% placebo). Risk for hospitalized HF was low and not significantly greater in pioglitazone compared with placebo groups (2.9% versus 2.3%, P=0.36). Older age, atrial fibrillation, hypertension, obesity, edema, high C-reactive protein, and smoking were risk factors for HF. However, the effect of pioglitazone did not differ across levels of baseline HF risk (hazard ratio [95% CI] for pioglitazone versus placebo for patients at low, moderate, and high risk: 1.03 [0.61-1.73], 1.10 [0.56-2.15], and 1.08 [0.58-2.01]; interaction P value=0.98). HF risk was increased in patients with versus those without incident myocardial infarction in both groups (pioglitazone: 31.4% versus 2.7%; placebo: 25.7% versus 2.4%; P<0.0001). Edema, dyspnea, and weight gain in the trial did not predict HF hospitalization but led to more study drug dose reduction with a lower mean dose of pioglitazone versus placebo (29±17 mg versus 33±15 mg, P<0.0001). Pioglitazone reduced the composite outcome of stroke, myocardial infarction, or hospitalized HF (hazard ratio, 0.78; P=0.007). CONCLUSIONS: In IRIS, with surveillance and dose adjustments, pioglitazone did not increase the risk of HF and conferred net cardiovascular benefit in patients with insulin resistance and cerebrovascular disease. The risk of HF with pioglitazone was not modified by baseline HF risk. The IRIS experience may be instructive for maximizing the net benefit of this therapy. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00091949.

Distance from Home to Research Center: A Barrier to In-Person Visits but Not Treatment Adherence in a Stroke Trial.

BACKGROUND AND PURPOSE: Clinical trials often seek to enroll patients from both urban and rural areas to safeguard the generalizability of results. However, maintaining contact with patients who live away from a recruitment site, including rural areas, can be challenging. In this research we examine the effect of distance between patient and study centers on treatment adherence and retention. METHODS: Secondary analysis of 2,466 participants in the Insulin Resistance Intervention after Stroke trial who were enrolled from research sites in the United States. Driving distance between the zipcodes of patient's reported place of residence and the study center was calculated. Outcome measures were loss to follow-up, completion of annual in-person visits, adherence to preventive therapy, and adherence to study drug in the first 3 years of participation. Logistic regression models were used to adjust for confounders. RESULTS: Distance from residence to research center was not associated with loss to follow-up, adherence to study drug, or adherence to preventive therapy (p > 0.05 for each). However, patients who lived farther from the research center (>120 miles), compared to patients who lived closer (<60 miles), were less likely to complete the second annual in-person visit (62 vs. 81%; adjusted OR 0.48; 95% CI 0.31-0.75) and third visit (53 vs. 75%; adjusted OR 0.44; 95% CI 0.29-0.67). CONCLUSIONS: Distance between patient and study center was an independent predictor of missed in-person visits but not with adherence to study treatment or preventive care.

Pioglitazone Prevents Stroke in Patients With a Recent Transient Ischemic Attack or Ischemic Stroke: A Planned Secondary Analysis of the IRIS Trial (Insulin Resistance Intervention After Stroke).

BACKGROUND: The IRIS trial (Insulin Resistance Intervention after Stroke) demonstrated that pioglitazone reduced the risk for a composite outcome of stroke or myocardial infarction among nondiabetic patients with insulin resistance and a recent stroke or transient ischemic attack. The current planned secondary analysis uses updated 2013 consensus criteria for ischemic stroke to examine the effect of pioglitazone on stroke outcomes. METHODS: Participants were randomly assigned to receive pioglitazone (45 mg/d target dose) or placebo within 180 days of a qualifying ischemic stroke or transient ischemic attack and were followed for a maximum of 5 years. An independent committee, blinded to treatment assignments, adjudicated all potential stroke outcomes. Time to first stroke event was compared by treatment group, overall and by type of event (ischemic or hemorrhagic), using survival analyses and Cox proportional hazards models. 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. Pioglitazone was associated with a reduced risk for any stroke at 5 years (8.0% in comparison with 10.7% for the placebo group; hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.60-0.94; log-rank P=0.01). Pioglitazone reduced risk for ischemic strokes (HR, 0.72; 95% CI, 0.57-0.91; P=0.005) but had no effect on risk for hemorrhagic events (HR, 1.00; 95% CI, 0.50-2.00; P=1.00). CONCLUSIONS: Pioglitazone was effective for secondary prevention of ischemic stroke in nondiabetic patients with insulin resistance. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00091949.

Effects of pioglitazone on cognitive function in patients with a recent ischaemic stroke or TIA: a report from the IRIS trial.

INTRODUCTION: Patients with cerebrovascular disease are at increased risk for cognitive dysfunction. Modification of vascular risk factors, including insulin resistance, could improve poststroke cognitive function. METHODS: In the Insulin Resistance Intervention after Stroke (IRIS) trial, patients with a recent ischaemic stroke or transient ischaemic attack (TIA) were randomised to pioglitazone (target 45 mg daily) or placebo. All patients were insulin resistant based on a Homeostasis Model Assessment-Insulin Resistance score >3.0. For this preplanned analysis of cognitive function, we examined the Modified Mini-Mental State Examination (3MS) score (maximum score, 100) during follow-up. Patients were tested at baseline and annually for up to 5 years. Longitudinal mixed model methods were used to compare changes in the 3MS over time. RESULTS: Of the 3876 IRIS participants, 3398 had a 3MS score at baseline and at least once during follow-up and were included in the analysis. Median 3MS score at baseline was 97 (IQR 93-99). The average overall least squared mean 3MS score increased by 0.27 in the pioglitazone group and by 0.29 in the placebo group (mean difference between treatment groups -0.02; 95% CI -0.33 to 0.28, p=0.88). CONCLUSIONS: Among insulin-resistant patients with a recent ischaemic stroke or TIA, pioglitazone did not affect cognitive function, as measured by the 3MS, over 5 years. TRIAL REGISTRATION: ClinicalTrials.gov NCT00091949; Results.

Targeting Pioglitazone Hydrochloride Therapy After Stroke or Transient Ischemic Attack According to Pretreatment Risk for Stroke or Myocardial Infarction.

Importance: There is growing recognition that patients may respond differently to therapy and that the average treatment effect from a clinical trial may not apply equally to all candidates for a therapy. Objective: To determine whether, among patients with an ischemic stroke or transient ischemic attack and insulin resistance, those at higher risk for future stroke or myocardial infarction (MI) derive more benefit from the insulin-sensitizing drug pioglitazone hydrochloride compared with patients at lower risk. Design, Setting, and Participants: A secondary analysis was conducted of the Insulin Resistance Intervention After Stroke trial, a double-blind, placebo-controlled trial of pioglitazone for secondary prevention. Patients were enrolled from 179 research sites in 7 countries from February 7, 2005, to January 15, 2013, and were followed up for a mean of 4.1 years through the study's end on July 28, 2015. Eligible participants had a qualifying ischemic stroke or transient ischemic attack within 180 days of entry and insulin resistance without type 1 or type 2 diabetes. Interventions: Pioglitazone or matching placebo. Main Outcomes and Measures: A Cox proportional hazards regression model was created using baseline features to stratify patients above or below the median risk for stroke or MI within 5 years. Within each stratum, the efficacy of pioglitazone for preventing stroke or MI was calculated. Safety outcomes were death, heart failure, weight gain, and bone fracture. Results: Among 3876 participants (1338 women and 2538 men; mean [SD] age, 63 [11] years), the 5-year risk for stroke or MI was 6.0% in the pioglitazone group among patients at lower baseline risk compared with 7.9% in the placebo group (absolute risk difference, -1.9% [95% CI, -4.4% to 0.6%]). Among patients at higher risk, the risk was 14.7% in the pioglitazone group vs 19.6% for placebo (absolute risk difference, -4.9% [95% CI, -8.6% to 1.2%]). Hazard ratios were similar for patients below or above the median risk (0.77 vs 0.75; P = .92). Pioglitazone increased weight less among patients at higher risk but increased the risk for fracture more. Conclusions and Relevance: After an ischemic stroke or transient ischemic attack, patients at higher risk for stroke or MI derive a greater absolute benefit from pioglitazone compared with patients at lower risk. However, the risk for fracture is also higher. Trial Registration: clinicaltrials.gov Identifier: NCT00091949.