Among millions of persons worldwide who survive an ischemic stroke or transient ischemic attack (TIA) each year, a major source of morbidity and mortality is recurrent stroke and myocardial infarction. Within 5 years of the initial event, 18-25% of patients will have a recurrent stroke, 9-10% will have a myocardial infarction, and 10-12% will die from one of these conditions. Prevention of further vascular events, therefore, is of major importance in reducing the morbidity and mortality of stroke and TIA. Current strategies to prevent recurrent vascular events include antiplatelet therapy, hypertension control, anticoagulation, lipid management, and carotid endarterectomy. Despite these effective strategies, each year 4-8% of suitably treated patients still experience recurrent vascular events. New therapies are urgently needed. The Insulin Resistance Intervention after Stroke (IRIS) trial is a randomized, double-blind, placebo-controlled study that is seeking to meet this need. IRIS is testing the effectiveness of pioglitazone for lowering the risk for stroke or myocardial infarction among men and women with a recent ischemic stroke or TIA and insulin resistance. Pioglitazone is a medication that lowers insulin resistance. Insulin resistance is a common, novel risk factor for stroke and other vascular diseases. It is also, along with failed pancreatic secretion of insulin, one of the 2 main causes of diabetes. Pioglitazone prevents diabetes, but its affect on vascular events, including stroke and myocardial infarction, are unproven. Eligible patients for IRIS are at least 40 years of age, non-diabetic, and insulin resistant according to an index based on fasting insulin and glucose values. Recruitment began in 2004, and 1,458 patients from over 90 sites in 3 countries have been randomized. Recruitment of 3,136 participants will be completed in 2010. All patients will be followed for a minimum of 3 years (average of 4). Assuming an outcome rate of 27% at 4 years for placebo recipients, IRIS has 90% power to detect a 20% reduction in risk for the primary endpoints of fatal and non-fatal stroke and myocardial infarction.

Public Health Relevance

Stroke is the 3rd leading cause of death in the US and the 2nd leading cause worldwide. The IRIS trial will test a new strategy, the treatment of insulin resistance in non-diabetic subjects, for preventing stroke and myocardial infarction after ischemic stroke or TIA. Since insulin resistance is estimated to affect 50% of stroke patients, this innovative treatment has the potential to benefit a large number of patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01NS044876-09
Application #
8382444
Study Section
Special Emphasis Panel (ZNS1-SRB-R)
Project Start
Project End
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
9
Fiscal Year
2012
Total Cost
$7,649,978
Indirect Cost
$1,313,639
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Yaghi, Shadi; Furie, Karen L; Viscoli, Catherine M et al. (2017) Pioglitazone Prevents Stroke in Patients with a Recent TIA or Ischemic Stroke: A Planned Secondary Analysis of the IRIS Trial. Circulation :
Epstein, Katherine A; Viscoli, Catherine M; Spence, J David et al. (2017) Smoking cessation and outcome after ischemic stroke or TIA. Neurology 89:1723-1729
Kernan, Walter N; Viscoli, Catherine M; Dearborn, Jennifer L et al. (2017) Targeting Pioglitazone Hydrochloride Therapy After Stroke or Transient Ischemic Attack According to Pretreatment Risk for Stroke or Myocardial Infarction. JAMA Neurol 74:1319-1327
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Inzucchi, Silvio E; Viscoli, Catherine M; Young, Lawrence H et al. (2017) Response to Comment on Inzucchi et al. Pioglitazone Prevents Diabetes in Patients With Insulin Resistance and Cerebrovascular Disease. Diabetes Care 2016;39:1684-1692. Diabetes Care 40:e47-e48
Young, Lawrence H; Viscoli, Catherine M; Curtis, Jeptha P et al. (2017) Cardiac Outcomes After Ischemic Stroke or Transient Ischemic Attack: Effects of Pioglitazone in Patients With Insulin Resistance Without Diabetes Mellitus. Circulation 135:1882-1893
Young, Lawrence H; Viscoli, Catherine M; Inzucchi, Silvio E et al. (2017) Response by Young et al to Letters Regarding Article, ""Cardiac Outcomes After Ischemic Stroke or Transient Ischemic Attack: Effects of Pioglitazone in Patients With Insulin Resistance Without Diabetes Mellitus"". Circulation 136:1567-1568
Xu, Jin; Viscoli, Catherine M; Ford, Gary A et al. (2016) A Diagnostic Score for Insulin Resistance in Nondiabetic Patients with Ischemic Stroke or Transient Ischemic Attack. J Stroke Cerebrovasc Dis 25:1705-1712
Kernan, Walter N; Viscoli, Catherine M; Furie, Karen L et al. (2016) Pioglitazone after Ischemic Stroke or Transient Ischemic Attack. N Engl J Med 374:1321-31
Stuart, Amber C; Sico, Jason J; Viscoli, Catherine M et al. (2016) Taking care of volunteers in a stroke trial: a new assisted-management strategy. Stroke Vasc Neurol 1:108-114

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