Trial Design

Pioglitazone for secondary prevention after ischemic stroke and transient ischemic attack: Rationale and design of the Insulin Resistance Intervention after Stroke Trial Catherine M. Viscoli, PhD, a Lawrence M. Brass, MD, a,n Antonio Carolei, MD, b Robin Conwit, MD, c Gary A. Ford, FRCP, d Karen L. Furie, MD, MPH, e Mark Gorman, MD, f Peter D. Guarino, PhD, g,h Silvio E. Inzucchi, MD, a Anne M. Lovejoy, PA-C, a Mark W. Parsons, MD, i Peter N. Peduzzi, PhD, g,h Peter A. Ringleb, MD, j Gregory G. Schwartz, MD, PhD, k J. David Spence, MD, l David Tanne, MD, m Lawrence H. Young, MD, a and Walter N. Kernan, MD a, on behalf of the IRIS Trial investigators New Haven, CT; L’Aquila, Italy; Bethesda, MD; Oxford, United Kingdom; Providence, RI; Burlington, VT; West Haven, CT; Newcastle, Australia; Heidelberg, Germany; Denver, CO; Ontario, Canada; and Tel Aviv, Israel

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 N3.0 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. (Am Heart J 2014;168:823-829.e6.)

From the aYale University School of Medicine, New Haven, CT, bUniversity of L’Aquila, L’Aquila, Italy, cNational Institute of Neurological Disorders and Stroke, Bethesda, MD, d Oxford University, Oxford, United Kingdom, eAlpert Medical School of Brown University, Providence, RI, fUniversity of Vermont School of Medicine, Burlington, VT, gCooperative Studies Program Coordinating Center, VA Connecticut Healthcare System, West Haven, CT, hYale School of Public Health, New Haven, CT, iUniversity of Newcastle, Newcastle, Australia, jUniversity of Heidelberg, Heidelberg, Germany, kVA Medical Center and University of Colorado School of Medicine, Denver, CO, lUniversity of Western Ontario, London, Ontario, Canada, and mTel Aviv University, Tel Aviv, Israel. n

Deceased March 8, 2006. US Food & Drug Administration Investigational New Drug: 64,622; EudraCT No. 2008005546-23. Clinical trial registration: ClinicalTrials.gov no. NCT00091949. Submitted May 22, 2014; accepted July 11, 2014. Reprint requests: Catherine M. Viscoli, PhD, 2 Church St South, Suite 515, New Haven, CT 06519.

E-mail: [email protected] 0002-8703 © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2014.07.016

Background Stroke is the second leading cause of death and the third leading cause of disability worldwide. 1-3 Despite effective strategies, including antithrombotic therapy, statins, blood pressure reduction, and carotid revascularization, survivors of ischemic stroke face a high risk for myocardial infarction (MI) and recurrent stroke. 4,5 Transient ischemic attacks (TIAs) produce less immediate disability than stroke but have a similar risk of subsequent cardiovascular events. 6 Insulin resistance affects almost all patients with type 2 diabetes mellitus (DM2) and a majority of nondiabetic patients with ischemic stroke or TIA. 7,8 In epidemiological research, insulin resistance has been associated with increased risk for coronary heart disease, stroke, and several vascular risk factors including hypertension, dyslipidemia, dysglycemia, vascular inflammation, endothelial dysfunction, hypercoagulability, and abnormal

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Table I. Final inclusion and exclusion criteria Inclusion criteria Ischemic stroke or TIA within 6 months of randomization Insulin resistance as defined by HOMA-IR N3.0 Age ≥40 years at randomization⁎ Ability and willingness to provide informed consent Exclusion criteria Stroke or TIA related to structural cardiac lesion† Stroke related to head trauma, proximal arterial dissection, or medical procedures‡ Diabetes mellitus§ CHF (NYHA class 1-4) or history of CHF History of bladder cancer or high risk for bladder cancer║ Active liver disease¶ Inability to participate in follow-up activities Irreversible medical conditions with predicted survival b4 years Oral or patch estrogen contraceptive use Ongoing use of oral corticosteroids History of intolerance to a TZD Pregnancy, desire to become pregnant, or currently breastfeeding Current participation in conflicting clinical trial# ALT N2.5 upper limit of normal Hemoglobin b8.5 g/dL Moderate-to-severe pitting edema of feet or legs Carotid surgery or carotid stenting procedure within 14 days of randomization Abbreviations: NYHA, New York Heart Association; ALT, Alanine aminotransferase. ⁎ Changed from 45 years in October 2007. † Mechanical aortic or mitral valves, left atrial thrombus or ventricular mural thrombus, atrial myxoma or other left-sided cardiac tumors, infective endocarditis, mitral stenosis associated with enlarged left atrium (N5.5 cm), spontaneous echo contrast, or valvular atrial fibrillation. ‡ Stroke within 24 hours of carotid endarterectomy, percutaneous coronary interventional procedure, CABG, intraaortic balloon pump, valvuloplasty, left-sided electrophysiologic procedures, or cardioversion. § Outpatient use of diabetes medication for diagnosis of diabetes in 90 days preceding screening test or fasting plasma glucose N125 mg/dL (confirmed on repeat testing) or HgbA1c ≥7.0% on screening test. ║ Current uninvestigated macroscopic hematuria, prior cyclophosphamide exposure, or irradiation to pelvic region. ¶ Known liver disease with cirrhosis, significant cholestasis, portal hypertension, hepatic encephalopathy, hepatic synthetic dysfunction, or expected significant loss of liver function during study. Patients with active hepatitis B were ineligible based on an empirical recommendation from the manufacturer of pioglitazone. # Trial with any of following: intervention known to affect the incidence of stroke or MI or that is an experimental drug, outcome that includes stroke or MI, exclusion for participation in another trial.

adipose tissue distribution and biology. 9-12 Based on these associations and data from preliminary therapeutic studies, investigators have hypothesized that modification of insulin resistance may reduce the incidence of stroke and MI. Strategies to improve insulin resistance include nutritional changes, exercise, weight reduction, and medications such as metformin or thiazolidinediones (TZD). The therapeutic potential of pioglitazone, a TZD used in the treatment of DM2, has been demonstrated in research showing that this agent has profound effects on numerous biological events related to the insulin resistant state, including inflammation, vascular cell proliferation, dyslipidemia, vascular lesion formation, and thrombosis.

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In diabetic patients, pioglitazone reduces insulin resistance and improves glycemic control, favorably modifies plasma lipid concentrations, reduces the progression of atherosclerosis in the carotid arteries, 13 and may improve cardiovascular outcomes. 14,15 In the PROactive trial, among a subgroup of diabetic patients with a history of prior stroke, pioglitazone was associated with a significant reduction in the risk for recurrent stroke. 16 In nondiabetic patients, pioglitazone has been shown to increase insulin sensitivity 17 and reduce the rate of progression to DM2. 18 The IRIS Trial is testing the hypothesis that treatment with pioglitazone will reduce risk for stroke and MI in nondiabetic, insulin-resistant patients. The selection of a nondiabetic study population is a novel and important aspect of the trial design, which addresses the risk of metabolic disturbances in patients with vascular disease before the onset of overt hyperglycemia. Because pioglitazone reduces both insulin resistance and circulating glucose, the exclusion of patients with established DM2 also results in a more specific test of the effect of lowering insulin resistance apart from the treatment of hyperglycemia. This exclusion also reduces the potential for TZD use in the control arm and for differential use of other diabetic treatments in the compared groups that could confound assessment of the study treatment.

Design Study objective. The IRIS (www.clinicaltrials. gov NCT00091949) is an investigator-initiated, international, multicenter, randomized, double-blind, placebocontrolled study in 3,876 insulin-resistant, nondiabetic patients with a recent ischemic stroke or TIA. The primary objective is to evaluate whether pioglitazone, initiated within 6 months of an ischemic stroke or TIA, reduces the incidence of subsequent stroke and MI. The study is approved in each participating center by the responsible ethics committee. The IRIS trial is funded by the US National Institute of Neurological Disorders and Stroke, award number U01 NS 44876. Takeda Pharmaceuticals USA (Deerfield, IL) provides study medication and funds the storage of blood from a subgroup of IRIS participants. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper, and its final contents. Study population. Inclusion and exclusion criteria are shown in Table I. Eligible men and women were aged ≥40 years and had a recent ischemic stroke or TIA, without a prior or current diagnosis of diabetes. A qualifying ischemic stroke was defined by focal neurologic symptoms or signs persisting for ≥24 hours and/or associated with a new area of infarction on brain imaging in an appropriate location. Patients with isolated monocular symptoms were required to have acute parenchymal ischemic abnormalities on brain imaging. After initiation of recruitment in January 2005, the protocol was

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Table II. Protocol adaptations Issue Index neurologic event

CHF

Change

Rationale

November 2005 Removal of requirement that patients with atrial fibrillation have lacunar syndrome or ipsilateral carotid stenosis; patients with atrial fibrillation eligible if no mitral stenosis. April 2006 Inclusion of selected TIA syndromes. December 2007 Inclusion of nonfocal strokes. December 2008 Inclusion of nonambulatory patients if baseline wheelchair/bed weight obtained and reweighing possible. December 2007 Exclusion of patients with NYHA class 2 CHF symptoms at all sites.

December 2008 Exclusion of patients with history of CHF (NYHA class 1-4).

Bladder cancer

January 2007 Exclusion of patients with history of bladder cancer.

August 2011 Exclusion of patients with cyclophosphamide or pelvic radiation exposure or uninvestigated macroscopic hematuria.

Diabetes outcome January 2007 event Permit deviations from ADA criteria.

Sample size Drug dosing

December 2008 Permit glucose measures obtained by glucometer in health care setting. February 2011 Increase in sample size and extension of follow-up. August 2011 Restriction of study medication dose to 15 mg for participants also taking gemfibrozil.

Substantial proportion of recurrent strokes in patients with atrial fibrillation attributable to noncardioembolic etiologies.

Expand applicability of results and pool of potential participants. Bring stroke definition into harmony with newer international criteria. Expand range of stroke severity and generalizability of trial results.

Revision of pioglitazone US package insert in September 2007 to include “black box” warning based on postmarketing adverse event reports that drug may cause or exacerbate CHF in some patients and recommendation against use in patients with symptomatic CHF. Pragmatic consideration that these patients are at increased risk for heart failure recurrence, which would lead to study medication discontinuation and planned expansion of recruitment network to Europe, where pioglitazone not used in patients with history of CHF. Revision of pioglitazone US package insert in November 2006 to include data from two 3-year clinical trials that showed a disparity in incidence of bladder cancers in diabetic patients assigned to pioglitazone versus comparator drugs. Revision of pioglitazone US package insert in July 2011 to include description of 2 observational studies that reported an association between long-term use of pioglitazone for diabetes and increased risk for bladder cancer and recommendation against use in persons with bladder cancer. European Medicine Agency recommended similar changes and included unexplained macroscopic hematuria as contraindication for pioglitazone. Evolving practice patterns, whereby diabetes may be diagnosed and medications prescribed after single fasting test or in hospitalized patients. Current medical practice patterns in community and need to preserve face value of outcome results. DSMB instructions following first interim analysis. Newly recognized interaction that coadministration may increase serum concentration of pioglitazone.

Abbreviation: ADA, American Diabetes Association.

amended in November 2005 to allow enrollment of patients with nonvalvular atrial fibrillation. In 2006, eligibility was further broadened to include selected TIA syndromes. A qualifying TIA was defined as an acute neurologic deficit attributable to brain ischemia that lasted ≥10 minutes but b24 hours, without imaging evidence of acute cerebral infarction. To enroll patients with a high likelihood of a vascular etiology for their symptoms, eligible TIA deficits were restricted to hemiplegia or hemiparesis, monoplegia or monoparesis, and a language disturbance other than isolated dysarthria. 19 In 2007, eligibility was extended to patients with stroke manifest by nonfocal neurologic symptoms (eg, dizziness, confusion, and headache) if the symptoms lasted ≥24 hours and were associated with a focal abnormality

on diffusion weighted magnetic resonance imaging (MRI) (see Table II for full timeline and rationale for protocol modifications). The Homeostatis Model Assessment–Insulin Resistance (HOMA-IR) (calculated as [fasting insulin, μU/mL × fasting glucose, mmol/L]/22.5 20) was used to identify patients with insulin resistance. Homeostatis Model Assessment– Insulin Resistance correlates with physiologic tests of insulin resistance, such as the hyperinsulinemic euglycemic clamp and intravenous glucose tolerance tests but is based on a simple blood sample and is practical for use in a large, multicenter trial. It has shown significant associations with glucose intolerance, 21 progression to DM2, 22,23 metabolic syndrome, 24 and cardiovascular disease. 25,26 A HOMA-IR threshold of N3.0 was chosen

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Table III. Timetable of assessments M

Physical examination⁎ Medical history Blood test Hemoglobin HbA1c Alanine aminotransferase Fasting glucose Fasting lipid profile Fasting insulin HS C-reactive protein NIH Stroke Scale Medication inventory Modified mini-mental examination Lifestyle survey† Safety and outcome screening ‡ Study medication dose changes Study medication resupply

Screening

Baseline

X X

X

Wk 2, 4, 6, 8, 10, 12

4

8

X X X X X X X X X X X X 4 and 8 weeks 12 weeks

X

Q 12 M

Exit

X

X

X

X X X X X

X X X

X X

X X

X X

X X

12

Q4M

X

X X

X

X X

X X

X

X

X

X

X

Abbreviations: Q4M, every 4 months; Q12M, annually; HS, high-sensitivity; NIH, National Institutes of Health. ⁎ Blood pressure, weight, height, edema grade, and waist and hip measurements. † Tobacco use, alcohol use, and exercise habits. ‡ Self-reported weight, edema symptoms, shortness of breath, muscle aches, macroscopic hematuria; new diagnoses of stroke, MI, diabetes, CHF, cancer, fracture, macular edema; all hospitalizations.

to define insulin resistance because this value represented the highest quartile of values among nondiabetic populations in research available at the initiation of IRIS. 27 Because of the known potential for TZD drugs to precipitate or worsen congestive heart failure (CHF), patients with New York Heart Association class 3 or 4 heart failure were excluded, although those with class 2 CHF (symptomatic with moderate activity) were initially eligible at US sites if their ejection fraction was ≥40%. In 2007, based on updated prescribing guidelines for pioglitazone, patients with symptomatic CHF were no longer permitted to enroll, and, in 2008, patients with any history of CHF were excluded from participation. Patients with moderate or severe lower extremity edema were also excluded because pioglitazone can also cause edema. Additional external developments during the trial led to several protocol modifications to ensure the safety of participants and conformity with evolving regulations. When IRIS began in 2005, there was no evidence to suggest an association between pioglitazone treatment and bladder cancer in humans. With the emergence of data from other trials suggesting a possible imbalance of bladder cancer in pioglitazone-treated diabetic patients, the IRIS protocol was revised in 2007 to minimize potential risk by excluding enrollment of patients with a history of bladder cancer and, in 2011, those with specific risk factors for bladder cancer, such as prior pelvic radiation or cytoxan exposure or uninvestigated macroscopic hematuria.

Study procedures. Patients providing informed consent underwent a screening interview, physical examination, and fasting blood test (Table III). Because insulin resistance may be impaired transiently after a cerebrovascular event, 28 the screening blood test to measure HOMAIR was conducted a minimum 14 days after the index stroke or TIA. Blood samples were processed centrally by Esoterix Inc. (Cranford, NJ; Burlington, NC) or an affiliate laboratory. The Linco (St. Charles, MO) human insulinspecific radioimmunoassay (RIA) was used at the laboratories in North America and Australia to measure circulating insulin concentrations. Because this assay was not available at the laboratories in Europe and Israel, the Linco animal serum-free enzyme-linked immunosorbent assay was used and results converted to RIA values by means of an internal LINCO correlation equation (insulin RIA [μU/mL] = 1.1056 × (insulin enzyme-linked immunosorbent assay [ulU/mL]) + 2.1494). Patients with HOMA-IR N3.0 and no excluded conditions were randomly assigned in a 1:1 ratio to initial treatment with one 15 mg pioglitazone or placebo tablet daily by mouth. Placebo and active tablets were identical in appearance and texture. Randomization was performed using a random permuted block design with variable block sizes stratified by site. To conceal the allocation sequence, randomization lists were kept only at the central pharmacy and the statistical center. The Investigational Drug Service at Yale-New Haven Hospital prepared all medication bottles, including starter supplies that were stored at the research sites. At the baseline visit,

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Table IV. Trial outcomes⁎ Primary Outcome Fatal or nonfatal stroke or MI Secondary outcomes Stroke (fatal or non-fatal) Acute coronary syndrome (MI or unstable angina) Diabetes onset Cognitive decline Stroke, MI, or severe CHF All-cause mortality ⁎ Outcome criteria are shown in Appendix.

a structured interview was administered, and the starter bottle with the participant’s assigned randomization number was dispensed. Follow-up interviews were scheduled every 2 weeks during the first 3 months. Study medication dose was increased at 4 weeks to 2 tablets daily (pioglitazone 30 mg or matching placebo) and at 8 weeks to 3 tablets daily (pioglitazone 45 mg or matching placebo). Participants at full protocol dose were supplied with pioglitazone 45 mg or matching placebo tablets at 12 weeks. Study medication is permanently discontinued if a participant develops CHF, nontraumatic fractures on 2 occasions involving bones other than the fingers and toes, bladder cancer, or macular edema. Dose can be reduced to manage side effects that are possibly drug related (eg, weight gain and edema). Adherence is calculated from pill counts of returned bottles as milligrams taken compared with milligrams prescribed per protocol, with zero adherence imputed for any periods off-drug. After month 4, participants are contacted every 4 months. Annual in-person assessments include a physical examination, Modified Mini-Mental State (3MS) test, 29 and fasting blood test. Participants who experience a stroke or MI are maintained on study medication. The IRIS investigators monitor vascular risk factors, report them to participants and physicians annually, and encourage participants to achieve their treatment goals, but the provision of standard secondary preventive care is the responsibility of personal physicians. Participants are followed for up to 5 years or until the last scheduled contact falling before the common trial end date (July 1, 2015), whichever comes first. Trial outcomes. The primary outcome is time to first occurrence of stroke or MI. Secondary outcomes are shown in Table IV. Clinical event committees for adjudicating neurology, cardiology, and endocrinology events are composed of a chairperson and ≥3 specialists. Two reviewers adjudicate each potential outcome, with a third reviewer added if needed to reach a majority decision. Reviewers are blinded to treatment allocation and receive training in IRIS outcome criteria (Appendix). To provide comparability to other research, sensitivity analyses will be conducted using published revised definitions for stroke, 30 MI, 31 and diabetes. 32

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Safety outcomes of special interest include heart failure, bone fracture, and bladder cancer. During the course of the trial, several developments led to protocol and informed consent modifications (Table II). In 2006, a randomized trial reported a higher rate of fractures in women receiving rosiglitazone, another drug in the TZD class. 33 In March 2007, the manufacturer of pioglitazone alerted health care providers to a similar finding based on analysis of its clinical trial database. In response, in April 2007, the IRIS informed consent was revised to describe this potential new risk, and a query for fractures was added to interviews; enrolled participants were asked to complete a retrospective survey for fractures, and all participants are advised to follow standard recommendations to preserve bone health. The 2007 informed consent revision also described new information from clinical trials in humans that suggested an association between pioglitazone use and increased risk for bladder cancer. In 2011, after several observational studies reported higher rates of bladder cancer in diabetic patients treated with pioglitazone, 34,35 the informed consent was again revised and the protocol modified to exclude participants who may be at higher risk for bladder cancer. Enrolled participants who met criteria for higher bladder cancer risk were removed from study medication. Statistical considerations. When the study was planned, a sample size of 3,136 was calculated to provide 90% power to detect a 20% relative reduction in the 4-year cumulative rate of stroke and MI using a log-rank test, with a type I error of 5% (2 sided), and the following assumptions: linear recruitment over 36 months, 4-year primary outcome rate of 27% in placebo group, 1% losses to follow-up for the primary outcome per year, 5% change to off-drug from active arm per year, 1% cross-overs to active from placebo arm per year, and a minimum of 3 interim analyses using O’Brien-Fleming stopping boundaries for efficacy and futility. 36 Sample size calculation used the method of Lakatos, 37,38 and stopping boundaries were determined using EaSt 2000 software (Cytel Corporation, Cambridge, MA). 39-41 The stopping boundaries were designed to be flexible, and the actual timing of the interim analyses is based on data safety and monitoring board (DSMB) requests. Because enrollment fell below planning estimates, in July 2007 enrollment was extended to achieve the original sample size. In February 2011, based on the results of the first blinded interim analysis, the DSMB recommended increasing person years in the trial by further extension of recruitment to June 2012 and follow-up to June 2015. In mid-2012, the DSMB allowed recruitment to continue at selected high-recruiting sites to the end of 2012. Recruitment ended on January 15, 2013 with a cohort of 3,876 participants. Baseline characteristics of the enrolled cohort are shown in the Appendix. All analyses will be conducted using the intention-totreat principle (ie, according to participants’ original treatment assignment). The analysis of the primary outcome will be tested by the stratified log-rank

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statistic, 42 with a type I error of 0.05 (2 sided) experimentwide level of significance. Cumulative event rates will be calculated using the method of Kaplan-Meier. The treatment effect will be summarized as a hazard ratio from a Cox proportional hazards model with 95% CI adjusted for interim looks. 43 In a sensitivity analysis, a Cox model will be used to assess the effect of treatment adjusted for prespecified baseline features that may affect prognosis or treatment effect. The effect of treatment will also be examined in subgroups defined by age, sex, race, Hispanic ethnicity, history of hypertension, history of coronary heart disease, body mass index, fasting plasma glucose, highdensity lipoprotein (HDL) cholesterol, triglyceride, HOMAIR, hemoglobin A1c (HbA1c), and medication adherence via treatment by covariate interactions. Except for cognitive decline, secondary outcomes will be analyzed as time to first event in the same manner as the primary outcome. For cognitive decline, repeated measures of the 3MS will be analyzed by longitudinal mixed model methods. 44 For participants with a normal 3MS score (N90) at entry, a logistic model will be used to evaluate the effect of treatment on risk for cognitive decline (exit score b78). To provide control for multiplicity, the procedure of Hochberg 45 will be used to determine significance for secondary outcomes using an overall type I error of 0.05 (2 sided).

Discussion IRIS is the only trial to date to test the effect of an insulinsensitizing intervention on cardiovascular outcomes in nondiabetic patients or in patients with cerebrovascular disease. An earlier trial of pioglitazone for prevention of cardiovascular outcomes in DM2 patients found a nonsignificant reduction in the primary end point (all-cause mortality, nonfatal MI and stroke, acute coronary syndrome, coronary artery bypass graft [CABG], percutaneous coronary intervention, major leg amputation, or revascularization). However, there was a reduced risk for the more restricted and usual outcome of nonfatal MI and stroke and all-cause mortality (12.3% versus 14.4% in placebo; P = .03). Furthermore, among patients with a history of prior stroke, there was a reduced risk for recurrent stroke (5.6% versus 10.2% in placebo; P = .0085). 14,16 In contrast, trials of another insulin-sensitizing drug, rosiglitazone, have failed to demonstrate significant reductions in cardiovascular risk in DM2 patients. 45,46 Pioglitazone differs from rosiglitazone in that it has mild peroxisome proliferator-activated receptor-α effects as wells as Peroxisome proliferator-activated receptor-γ actions, which lead to a more favorable effect on plasma lipid levels. By testing pioglitazone in a nondiabetic population, IRIS differs in significant ways from these earlier trials. First, IRIS recognizes the prevalence of metabolic abnormalities in vascular disease patients before the onset of diabetes and postulates that modification of

insulin resistance at an earlier stage might have greater consequent cardiovascular benefit than treating hyperglycemia per se. Second, IRIS avoids the confounding effects of diabetes studies in which comparator groups either are assigned to other antidiabetic drugs or are subject to different levels of hyperglycemia, allowing a clearer evaluation of the effects of pioglitazone. Third, IRIS is the first stroke study to specifically test the effects of metabolic intervention. Because cardiovascular risk after stroke is related to insulin resistance, our study population with cerebrovascular disease may derive particular benefit from treatment with pioglitazone. Study results, expected in 2016, are likely to contribute significantly to our understanding of the complex interaction between vascular disease and metabolism.

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16. Wilcox R, Bousser M-G, Betteridge DJ, et al. Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke. Results from PROactive (PROspective pioglitAzone Clinical Trial in macroVascular Events 04). Stroke 2007;38:865-73. 17. Kernan WN, Inzucchi SE, Viscoli CM, et al. Pioglitazone improves insulin sensitivity among nondiabetic patients with a recent transient ischemic attack or ischemic stroke. Stroke 2003;34:1431-6. 18. DeFronzo RA, Tripathy D, Schwenke DC, et al. Pioglitazone for diabetes prevention in impaired glucose tolerance. N Engl J Med 2011;364:1104-15. 19. Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al. Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack. Lancet 2007;369:283-92. 20. Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and B-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412-9. 21. Haffner SM, Miettinen H, Stern MP. The homeostatic model in the San Antonio Heart Study. Diabetes Care 1997;20:1087-8. 22. Resnick HE, Jones K, Ruotolo G, et al. Insulin resistance, the metabolic syndrome, and risk of incident cardiovascular disease in non-diabetic American Indians. Diabetes Care 2003;26:861-7. 23. Haffner SM, Gonzalez C, Miettinen H, et al. A prospective analysis of the HOMA model. Diabetes Care 1996;19:1138-41. 24. Alexander CM, Landsman PB, Teutsch SM, et al. NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes 2003;52:1210-4. 25. Hanley AJG, Williams K, Stern M, et al. Homeostasis model assessment of insulin resistance in relation to the incidence of cardiovascular disease: the San Antonio Heart Study. Diabetes Care 2002;25:1177-84. 26. Hedblad B, Nilsson P, Engstrom G, et al. Insulin resistance in nondiabetic subjects is associated with increased incidence of myocardial infarction and death. Diabetes Med 2002;19:470-5. 27. Balkau B, Charles MA. for the European Group for the Study of Insulin Resistance (EGIR). Comment on the provisional report from the WHO consultation. Diabet Med 1999;16:442-3. 28. Huff TA, Lebovitz HE, Heyman A, et al. Serial changes in glucose utilization and insulin and growth hormone secretion in acute cerebrovascular disease. Stroke 1972;3:543-52.

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29. Teng EL, Shui HC. The modified mini mental state (3MS) examination. J Clin Psychiatry 1987;48:314-8. 30. Sacco RL, Kasner SE, Broderick J, et al. An updated definition of stroke for the 21st century. A statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke Council. Stroke 2013;44:2064-89. 31. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. J Am Acad Coll Cardiol 2012;60:2020-35. 32. Association AD. Standards of medical care in diabetes—2010. Diabetes Care 2010;33:S11-61. 33. Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355:2427-43. 34. Lewis J, Ferrara A, Peng T, et al. Relative risk of bladder cancer with pioglitazone for diabetes mellitus: mid-way report of a 10-year follow-up study. Pharmacoepidemiol Drug Saf 2010;19:S13. 35. Neumann A, Weill A, Ricordeau P, et al. Pioglitazone and risk of bladder cancer among diabetic patients in France: a population-based cohort study. Diabetologia 2012;55:1953-62. 36. O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979;35:549-56. 37. Lakatos E. Sample size determination in clinical trials with time-dependent rates of losses and noncompliance. Control Clin Trials 1986;7:189-99. 38. Lakatos E. Sample sizes based on the log-rank statistic in complex clinical trials. Biometrics 1988;44:229-41. 39. Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 1983;70:659-63. 40. DeMets DL, Lan KKG. Interim analysis: the alpha spending function approach. Stat Med 1994;13:1341-52. 41. Wang SK, Tsiatis AA. Approximately optimal one-parameter boundaries for group sequential trials. Biometrics 1987;43:193-9. 42. Kalbfleish J, Prentice R. The statistical analysis of failure time data. New York: John Wiley & Sons. 1980. 43. Cox DR. Regression models and life-tables. J R Stat Soc 1972;34: 187-202. 44. Diggle PJ, Liang K-Y, Zeger SL. Analysis of longitudinal data. Oxford: Clarendon Press. 1994. 45. Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika 1988;75:800-2.

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Appendix I. Protocol outcome definitions (primary and secondary outcomes) Fatal or nonfatal stroke or fatal or nonfatal MI were selected as the primary outcomes for the IRIS trial for three reasons. Firstly, they are the major vascular events contributing to morbidity and mortality after an initial ischemic stroke or TIA. Secondly, they have both been associated with insulin resistance, and treating insulin resistance may reduce risk for each of them. Thirdly, stroke and MI can be detected and verified with a high degree of accuracy. In addition, we will examine several end points other than stroke and MI as secondary end points. Definitions for all primary and secondary end points are as follows: Stroke. An outcome stroke is an acute neurological event with focal signs or symptoms lasting at least 24 hours, which represent a focal loss of brain function that can be attributed to a disturbance in one vascular distribution and for which no other cause is found. In addition, there must be at least a one-point increase in the NIH stroke scale in a previously normal section or an appropriate new or extended abnormality seen on CT or MRI. IRIS will count nontraumatic intracerebral and subarachnoid hemorrhage as outcomes in addition to ischemic events. Subdural and epidural hematoma are not included as part of the primary stroke outcome. A stroke is classified as fatal if death occurs within 30 days or if, in the opinion of the neurology review committee, death is a direct result of a physiological consequence of a stroke event. Myocardial infarction. Acute myocardial infarction will be diagnosed according to criteria modified from the 2000 Consensus Conference of the European and American Colleges of Cardiology. 46 MI events will be diagnosed based on patient symptoms and electrocardiogram changes, in conjunction with contemporary biochemical markers of myocardial necrosis (troponin or CK). Both acute ST-segment elevation and non–ST segment elevation MI will be combined as a primary outcome. An acute, evolving, or recent nonfatal MI will be diagnosed in the presence of a typical rise and gradual fall (troponin) or more rapid rise and fall (CK-MB) of biochemical markers of myocardial necrosis with at least one of the following: (a) ischemic symptoms, (b) development of pathologic Q waves on the ECG, (c) ECG changes indicative of ischemia (ST-segment elevation or depression), (d) coronary artery intervention (eg, angioplasty), (e) angiographic findings indicative of unstable plaque or thrombus in a coronary artery, or (f) cardiac imaging (perfusion or echocardiogram) suggestive of MI.

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Criteria for biochemical markers depend on whether the event was (a) spontaneous or in setting of (b) cardiac catheterization, angioplasty, or stenting; or (c) CABG. Biochemical markers will be considered indicative of necrosis when the CK-MB exceeds (a) 1.5, (b) 3.0, and (c) 5.0× ULN, respectively or troponin concentration exceeds (a) 2.0, (b) 5.0, and (c) 10× ULN, respectively. For participants who do not seek medical care at the time of acute symptoms, a recent nonfatal MI will be diagnosed in the presence of a history of ischemic symptoms and new Q waves on ECG or imaging data clearly indicative of new, focal myocardial damage. A fatality will be classified as “fatal MI” according to criteria from the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS),47 which requires that there be no noncardiac cause of death and one of the following: death within 30 days from the onset of symptoms of a definite acute myocardial infarction, witnessed unexpected sudden cardiac death within 1 hour of symptoms, death occurring N1 hour but b24 hours after collapse, and unwitnessed and unexpected death that is presumed to be sudden (in this case, there must be confirming autopsy data or preceding history of CHD events or symptoms). Acute coronary syndrome/unstable angina. Acute coronary syndrome (unstable angina, fatal, or nonfatal myocardial infarction) are a secondary outcome. The diagnosis of unstable angina will be based on the well-defined criteria from the AFCAPS/TexCAPS study.47 This diagnosis requires the absence of a diagnosis of myocardial infarction and the presence of new-onset, accelerated exertional, or rest chest pain (anginal in quality) lasting N5 minutes and at least one of the following: mildly elevated troponin values (b2× upper limit of normal), new or presumably new ST-segment deviation N0.5 mm in 2 or more leads, T-wave inversion N3mm in 3 leads, left bundle branch block, or abnormal stress testing. Abnormal stress testing is defined as N1 mm horizontal or down-sloping ST-segment depression in two or more leads with evidence of abnormalities in stress imaging or coronary angiography as described below (if imaging or angiography is obtained). Stress imaging evidence: •

•

Perfusion imaging (MIBI or thallium): a reversible perfusion defect with exercise or pharmacologic stress (adenosine, dipyridamole, and dobutamine) imaging; or Echocardiography: an inducible regional wall motion abnormality after exercise or pharmacologic stress. Angiographic evidence:

•

N70% stenosis in the LAD, circumflex, or RCA or one of their major branches, or N50% left main coronary artery stenosis.

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Diabetes mellitus. Diabetes mellitus will be classified based on American Diabetes Association guidelines. According to these guidelines, diabetes is diagnosed when one of three conditions is met: (1) the value of two fasting glucose measurements equal or exceed 126 mg/dL, (2) two random plasma glucose equals or exceeds 200 mg/dL in the presence of typical symptoms of diabetes, or (3) the plasma glucose equals or exceeds 200 mg/dL two hours after a 75 gram oral glucose load, confirmed on a repeat test. In practice, the oral glucose tolerance test is rarely used. For this reason and to reduce the burden of participating in the trial, we will classify a participant as having diabetes if one of the first two criteria is met. In addition, IRIS participants will be classified as diabetic in the presence of compelling indicators of hyperglycemia, even if requisite ADA testing is not performed. Specifically, patients will be classified as diabetic if any of the following three conditions is met: •

A physician diagnoses diabetes and prescribes an antidiabetic agent and one of the following test results is documented: • • • •

•

•

Fasting plasma glucose concentration equals or exceeds 126 mg/dL (7•0 mmol/L); Random plasma glucose concentration equals or exceeds 200 mg/dL (11•1 mmol/L); 2-hour OGTT glucose equals or exceeds 200 mg/dL (11.1 mmol/L); HbA1c equals or exceeds 7.0%.

Two fasting glucometer (capillary blood) glucose values obtained in a health-care setting (ie, not a home test) equal or exceed 151 mg/dL (8.4 mmol/L) (ie, 1.2 × 126 mg/dL [7 mmol/L]); Two random glucometer (capillary blood) glucose values obtained in a health-care setting (ie, not a home test) equal or exceed 240 mg/dL (13.2 mmol/L) (ie, 1.2 × 200 mg/dL [11 mmol/L]) in the presence of typical symptoms of hyperglycemia (eg, polyuria, polydipsia, weight loss, and blurry vision);

In the situation where blood glucose levels are only available from a glucometer (capillary blood), it is acceptable to use these data, but only if the test is performed in a health care setting (physician’s office, clinic, or skilled nursing facility), since proper standardization and use of the meter cannot be assumed with at-home testing. To be conservative, a margin of error of +20% has been incorporated, since the minimum acceptable accuracy for glucometer results is within 20% at glucose concentrations over 75 mg/dL. A diagnosis of diabetes that is made during a hospital admission will not be recognized unless one of the following two conditions is met:

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(1) The hospital admission was for a diabetic emergency, such as diabetic ketoacidosis or hyperosmolar hyperglycemic syndrome; (2) The patient was discharged on any antihyperglycemic agent and a HbA1c ≥7.0% was obtained during the hospitalization. All-cause mortality. All-cause mortality will serve as a routine check on safety. It is also a very objective, additional measure of treatment effectiveness. Cognitive decline. Decline in cognitive function will be measured as a change in mean score in the Modified Mini Mental State Examination (3MS). In a secondary analysis, we will restrict the analysis to participants who entered IRIS with a normal 3MS (N90) and define a significant decline as an exit score below 78, the customary criterion for significant impairment. 48 The reason to restrict this secondary analysis to participants with a normal baseline score is that any discrete change in score may have different importance for people with different baseline function. A fall of 12 points from normal to less than 78, however, is generally regarded as significant. Severe CHF. CHF episodes that result in hospital admission or death will be counted in a combined secondary outcome (along with stroke and MI). The composite outcome was added at the request of the DSMB to create a measurement of the net benefit of pioglitazone. Episodes of CHF are classified by members of the Cardiology Outcome Committee. In completing its assessment, the committee will be guided by usual practices in diagnosing heart failure, which require consideration of typical symptoms (shortness of breath, weight gain, edema, fatigue, dyspnea on exertion, and PND), signs (weight gain, pulmonary rales, JVP, edema, tachypnea, and tachycardia), test findings (eg, pulmonary edema on chest radiography and serum BNP concentration), and alternative diagnoses. Nonfatal episodes of CHF leading to emergency room visits or hospital stays less than 24 hours in duration will not be counted as secondary outcomes. (All adjudicated episodes of CHF, regardless of severity or resultant hospitalization, are reported to the data safety and monitoring board with other adverse events).

II. Outcomes for sensitivity analyses definitions

Stroke: 2013 AHA/ASA criteria for stroke. At the time the IRIS trial was initiated in 2004, it used a definition for stroke that was widely accepted at the time and based on clinical and imaging data: “For purposes of this trial, a stroke is an acute neurological event with focal signs or symptoms lasting at least 24 hours, which represent a focal loss of brain function that can be attributed to a disturbance in one vascular distribution and for

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which no other cause is found. In addition, there must be at least a one-point increase in the NIH stroke scale in a previously normal section or an appropriate new or extended abnormality seen on CT or MRI. . . . Subdural and epidural hematoma are not included as part of the primary stroke outcome.” This definition for stroke included nontraumatic subarachnoid hemorrhage and intracerebral hemorrhage.To account for advances in science and technology, in 2013, the American Heart Association/ American Stroke Association issued a statement for health care professionals describing an updated definition for stroke 30. The update was motivated by opinion that the older, standard WHO definition had been made obsolete by evidence that permanent injury can result from events lasting less than 24 hours. In addition, the AHA/ASA felt that a uniform definition was needed for purposes of clinical care and research. The resulting new AHA/ASA definition for stroke broadly includes symptomatic and asymptomatic events caused by CNS infarction, intracerebral hemorrhage, subarachnoid hemorrhage, and cerebral venous thrombosis. There is also a category of “stroke, not otherwise specified” that is defined by an episode of acute neurological dysfunction presumed to be caused by ischemia or hemorrhage, persisting N24 hours, or until death but without sufficient evidence to be classified as one of the above.” The most significant feature of the AHA/ASA updated definition and the only feature that affects IRIS relate to the definition of ischemic stroke as “an episode of neurological dysfunction caused by focal cerebral, spinal, or retinal infarction.” The definition for CNS infarction is based on: (1) Pathological, imaging, or other objective evidence of cerebral, spinal cord, or retinal focal ischemic injury in a defined vascular distribution; or (2) Clinical evidence of cerebral, spinal cord, or retinal focal ischemic injury based on symptoms persisting N24 hours or until death and other etiologies excluded (note: CNS infarction includes hemorrhagic infarctions, types I and II . . . ). Imaging evidence for infarction, according to the updated AHA/ASA criteria, includes findings from MRI or CT. The statement recognizes that MRI is more sensitive than CT scanning, particularly within first 12 hours but that neither is perfectly accurate. This updated definition, if applied to participants in the IRIS Trial, would likely result in more events being classified as stroke compared with the original IRIS definition. This is because the original IRIS definition requires symptoms or signs to last at least 24 hours, even in the presence of imaging evidence for infarction. The

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updated definition classifies an episode of focal neurological dysfunction as an ischemic stroke if there is evidence for infarction regardless of duration of symptoms. The updated definition for stroke caused by ICH (“Rapidly developing clinical signs of neurological dysfunction attributable to a focal collection of blood within the brain parenchyma or ventricular system that is not caused by trauma”) is identical to the IRIS definition, including the exclusion of subdural and epidural hematomas. The updated definition for stroke caused by SAH (“Rapidly developing signs of neurological dysfunction and/or headache because of bleeding into the subarachnoid space [the space between the arachnoid membrane and the pia mater of the brain or spinal cord], which is not caused by trauma”) is also identical to the current IRIS definition. The ancillary analysis for the primary outcome will define fatal and nonfatal stroke according to the AHA/ASA updated definition for stroke and represents a sensitivity analysis to show readers how our findings are affected by use of the more modern definition. It is important to note that the primary outcome for the IRIS Trial (ie, fatal or nonfatal MI plus fatal or nonfatal stroke) does not change and will still be classified and reported using the original IRIS protocol and its older stroke definition. We are not proposing to change the definition for the primary outcome. However, the sensitivity analysis will be reported to show the effect of the new criteria on IRIS findings. Myocardial infarction: 2012 ESC/ACCF/AHA/WHF criteria for MI. Since the IRIS trial was designed in 2004, two international consensus panels have revised the definition of myocardial infarction (MI). In 2000, the First Global MI Task Force had proposed that any troponin elevation in the setting of myocardial ischemia be interpreted as an indicator of necrosis and MI, but there was little early acceptance of this definition. In 2007, the Joint ESC/ ACCF/AHA/WHF Task Force reiterated this definition in the Universal Definition of Myocardial Infarction Consensus Document and further distinguished between different conditions that lead to MI (eg, type 1, spontaneous; type 2, imbalanced in balance of myocardial oxygen demand and supply; type 3, sudden unexpected cardiac death; type 4, infarction related to PCI or stent thrombosis; and type 5, infarction related to CABG). For spontaneous MI, the panel based the diagnosis on a rise or fall of cardiac biomarkers (preferably troponin) with at least one value above the 99th percentile upper reference limit (URL). This new cutoff for cardiac biomarkers was lower than the cutoff of 1.5 to 2.0× 99th percentile URL that had been commonly used in the past and was used for the IRIS primary outcome definition. The revised MI definition recognized progress in standardizing and improving cardiac troponin (cTn) as a specific biomarker of myocardial necrosis. The second Joint ESC/ACCF/AHA/WHF panel published the Third Universal Definition of Myocardial Infarction in

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2012. 31 This document further refined the definition of MI with the following additional changes: • Addition of “identification of an intracoronary thrombus by angiography or autopsy” in the list of evidence that could support the diagnosis of acute MI. o This criterion is consistent with the current IRIS criteria. • Minor changes in the criteria for qualifying ST-segment elevation based on gender and age. The revised criteria require new ST elevation at the J point in two contiguous leads with the cut-points: N0.1 mV in all leads other than leads V2 or V3, where the following cut points apply: N0.2 mV in men N40 years, N0.25 mV in men b40 years, or N0.15 mV in women. o These criteria have slight differences from the current IRIS criteria. • Revision of criteria for the diagnosis for sudden cardiac death or cardiac death when biomarkers are unavailable to require premorbid symptoms suggestive of myocardial ischemia and to remove mention of evidence from angiography or autopsy. The new criteria represent a gradual movement to require more specific evidence for a cardiac etiology before attributing sudden or unexpected death to myocardial infarction. o These criteria are more conservative than the current IRIS criteria, which attribute death to a MI if it is unwitnessed, there is no other identified cause, and it is presumed to be sudden (in this case there must be confirming autopsy data or, if an autopsy was not performed, a preceding history of CHD events or symptoms). • Change in the criterion for the diagnosis of MI in the setting of percutaneous coronary intervention from an elevation of cardiac biomarker values (preferably cTn) N3× 99th percentile URL to N5× 99th percentile URL in patients with normal baseline values or a rise of cardiac biomarker values N20% if the baseline values are elevated and are stable or falling. In addition, the diagnosis requires one of several other signs of myocardial injury: symptoms of ischemia, new ischemic ECG changes, persistent loss of patency of a coronary artery or side-branch, or imaging evidence of loss of function or viability.

•

o These cTn criteria (N5× 99th percentile URL) are the same as for IRIS. However, the IRIS criteria also allow for CK-MB N3× 99th percentile. IRIS does not require any other symptom or sign of myocardial injury in this setting. Change in the criterion for the diagnosis of MI in the setting of coronary bypass surgery from an elevation of cardiac biomarker values N5× 99th percentile URL to N10× 99th percentile URL. In addition, the diagnosis requires one of several other signs of myocardial injury: pathologic Q wave or LBBB, new graft or native vessel occlusion, or imaging evidence of loss of function or viability. o These new cTn criteria (N10× 99th percentile URL) are the same as the current IRIS criteria. However, the IRIS criteria also allow CK-MB N5× 99th percentile URL when cTn is not available. o IRIS does not require any other signs or symptoms of myocardial injury in these settings.

A summary of similarities and differences between the Third International Definition and the IRIS definition appear in online Appendix Supplementary Table. The 2012 revisions are expected to become the standard for diagnosis of myocardial infarction, although controversy continues about the clinical importance of infarcts associated with minimal troponin release. Troponin is an extremely sensitive marker of myocardial injury, and minimal levels of troponin release do not lead to impairment in cardiac function. Nonetheless, most studies are adopting the new criteria. To ensure comparability of the IRIS results to other research, we will perform an ancillary analysis to determine the impact of the Third International Definition of MI on IRIS findings. The ancillary analysis for the primary outcome will define fatal and nonfatal MI outcomes according to the newly revised definition for MI and represents a sensitivity analysis to show readers how our findings are affected by use of the more modern definition. It is important to note that the primary outcome for the IRIS Trial (ie, fatal or nonfatal MI plus fatal or nonfatal stroke) does not change and will still be classified and reported using the original IRIS protocol and its older MI definition. The sensitivity analysis will be reported to show the effect of the new criteria on IRIS findings.

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Supplementary Table. Comparison of Third International Definition for MI and IRIS criteria for MI Item

3rd international

Enzyme threshold N1× 99th upper percentile URL for Dx of Spontaneous MI Symptoms Symptoms of myocardial ischemia ECG: Q waves New Q waves N0.03 s and N0.1 mV deep or QS complex in leads I, II, aVL, aVF, or V4-V6 in any two leads of a contiguous lead grouping (I, aVL, V1-V6, II, III, aVF) ECG: LBBB New LBBB ECG: ST elevation New ST elevation at the J point in two contiguous leads with the cutpoints: N0.1 mV in all leads other than leads V2-V3, where the following cut points apply: N0.2 mV in men N40 years, N0.25 mV in men b40 years, or N0.15 mV in women ECT: ST New horizontal or down-sloping ST depression N0.05 mV in two depression contiguous leads and/or T inversion N0.1 mV in two contiguous leads with prominent R wave or R/S ratio N1 IC thrombus Angiographic findings or autopsy indicative of thrombus in coronary artery Imaging Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality Autopsy

Autopsy findings of coronary thrombus

IRIS Troponin N2× URL or CB-MK N1.5× URL

Symptoms of myocardial ischemia New Q waves N0.03 s in 2 or more contiguous leads

New LBBB New ST elevation at the J point in two or more contiguous leads with the cut-points N0.2 mV in leads V1-V3 and N0.1 mV in all other leads. New/presumed new ST depression N0.1 mV and/or T inversion N0.1 mV in two or more contiguous leads Angiographic findings indicative of thrombus in a coronary artery or unstable plaque Cardiac imaging clearly indicative of new focal myocardial damage (fixed perfusion defect or echo wall motion abnormality) Autopsy evidence of an acute MI

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Diabetes: 2010 ADA Criteria for Diabetes. In 2010, the ADA revised the criteria for diabetes to include hemoglobin A1c N6.5% (confirmed by repeat testing). To determine how the IRIS results would be affected by use of this revised definition, we will conduct a sensitivity analysis using the revised criteria. No other aspects of the IRIS DM outcome classification are affected.

III. Baseline features of IRIS participants (n = 3876) Baseline Feature 1 Demographics Age (years) Male Black race Clinical History Stroke at entry (vs TIA) Prior stroke (hx) Hypertension (hx) Coronary artery disease 2 Current smoker Physical Examination Weight (kg) BMI (kg/m 2) Waist circumference (cm) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Laboratory data Glucose (mmol/L) Insulin HOMA HbA1c (%) LDL cholesterol (mmol/L) HDL cholesterol (mmol/L) Triglycerides (mmol/L) C-reactive protein Lipid-lowering medications Statins Fibrates Other cholesterol meds Antiplatelet medications Aspirin Non-asa antiplatelet Oral anticoagulants

Mean + SD

No.

%

2538 442

65% 11%

3378 488 2770 462 622

87% 13% 71% 12% 16%

3186 111 249

82% 3% 6%

2839 1657 441

73% 43% 11%

63 (±11)

88 30 107 136 82

(±18) (±6) (±105) (±18) (±11)

5.45 22.4 5.44 5.8 2.27 1.22 1.59 4.71

(±0.55) (±10.2) (±2.74) (±0.4) (±0.81) (±0.33) (±0.82) (±8.77)

1 Missing data: race (25), clinical history (2), A1c (1), LDL (38), HDL (8), triglycerides (7), C-reactive protein (29), and mediations (2). 2 Self-reported history of hospitalization for MI, CABG, or coronary angioplasty.

Supplementary References 46. The Joint European Society of Cardiology/American College of Cardiology Committee. Myocardial infarction redefined—a consensus document of the joint European Society of Cardiology/American College of Cardiology Committee for the Redifinition of Myocardial Infarction. J Am Coll Cardiol 2000;36:959-69. 47. Downs JR, Beere PA, Whitney E, et al. Design and rationale of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/ TexCaps). Am J Cardiol 1997;80:287-93. 48. Bland RC, Newman SC. Mild dementia or cognitive impairment: the modified Mini-Mental State Examination (3MS) as a screen for dementia. Can J Psychiatry 2001;46:506-10.