title: Cardiac Outcomes After Ischemic Stroke or Transient Ischemic Attack: Effects of Pioglitazone in Patients With Insulin Resistance Without Diabetes Mellitus.
abstract: BACKGROUND
  Insulin resistance is highly prevalent among patients with atherosclerosis and is associated with an increased risk for myocardial infarction (MI) and stroke. The IRIS trial (Insulin Resistance Intervention after Stroke) demonstrated that pioglitazone decreased the composite risk for fatal or nonfatal stroke and MI in patients with insulin resistance without diabetes mellitus, after a recent ischemic stroke or transient ischemic attack. The type and severity of cardiac events in this population and the impact of pioglitazone on these events have not been described.
  
  
  METHODS
  We performed a secondary analysis of the effects of pioglitazone, in comparison with placebo, on acute coronary syndromes (MI and unstable angina) among IRIS participants. All potential acute coronary syndrome episodes were adjudicated in a blinded fashion by an independent clinical events committee.
  
  
  RESULTS
  The study cohort was composed of 3876 IRIS participants, mean age 63 years, 65% male, 89% white race, and 12% with a history of coronary artery disease. Over a median follow-up of 4.8 years, there were 225 acute coronary syndrome events, including 141 MIs and 84 episodes of unstable angina. The MIs included 28 (19%) with ST-segment elevation. The majority of MIs were type 1 (94, 65%), followed by type 2 (45, 32%). Serum troponin was 10× to 100× upper limit of normal in 49 (35%) and >100× upper limit of normal in 39 (28%). Pioglitazone reduced the risk of acute coronary syndrome (hazard ratio, 0.71; 95% confidence interval, 0.54-0.94;P=0.02). Pioglitazone also reduced the risk of type 1 MI (hazard ratio, 0.62; 95% confidence interval, 0.40-0.96; log-rankP=0.03), but not type 2 MI (hazard ratio, 1.05; 95% confidence interval, 0.58-1.91;P=0.87). Similarly, pioglitazone reduced the risk of large MIs with serum troponin >100× upper limit of normal (hazard ratio, 0.44; 95% confidence interval, 0.22-0.87;P=0.02), but not smaller MIs.
  
  
  CONCLUSIONS
  Among patients with insulin resistance without diabetes mellitus, pioglitazone reduced the risk for acute coronary syndromes after a recent cerebrovascular event. Pioglitazone appeared to have its most prominent effect in preventing spontaneous type 1 MIs.
  
  
  BACKGROUND
  URL: http://clinicaltrials.gov. Unique identifier: NCT00091949.
authors.affiliation: From Yale University School of Medicine, New Haven, CT (L.H.Y., C.M.V., J.P.C., S.E.I., A.M.L., D.L.J., S.E.P., W.N.K.); Denver VA Medical Center and University of Colorado School of Medicine (G.G.S., J.D.A.); Alpert Medical School of Brown University, Providence, RI (K.L.F., J.D.A.); Maine Medical Center, Portland (M.J.G.); National Institutes of Health/National Institute of Neurological Disorders and Stroke, Bethesda, MD (R.C.); University of Pennsylvania Perelman School of Medicine, Philadelphia (D.M.K.); and University of Rochester School of Medicine and Dentistry, NY (F.S.L.). lawrence.young@yale.edu.
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Young
authors.affiliation: From Yale University School of Medicine, New Haven, CT (L.H.Y., C.M.V., J.P.C., S.E.I., A.M.L., D.L.J., S.E.P., W.N.K.); Denver VA Medical Center and University of Colorado School of Medicine (G.G.S., J.D.A.); Alpert Medical School of Brown University, Providence, RI (K.L.F., J.D.A.); Maine Medical Center, Portland (M.J.G.); National Institutes of Health/National Institute of Neurological Disorders and Stroke, Bethesda, MD (R.C.); University of Pennsylvania Perelman School of Medicine, Philadelphia (D.M.K.); and University of Rochester School of Medicine and Dentistry, NY (F.S.L.).
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Viscoli
authors.affiliation: From Yale University School of Medicine, New Haven, CT (L.H.Y., C.M.V., J.P.C., S.E.I., A.M.L., D.L.J., S.E.P., W.N.K.); Denver VA Medical Center and University of Colorado School of Medicine (G.G.S., J.D.A.); Alpert Medical School of Brown University, Providence, RI (K.L.F., J.D.A.); Maine Medical Center, Portland (M.J.G.); National Institutes of Health/National Institute of Neurological Disorders and Stroke, Bethesda, MD (R.C.); University of Pennsylvania Perelman School of Medicine, Philadelphia (D.M.K.); and University of Rochester School of Medicine and Dentistry, NY (F.S.L.).
authors.forename: Jeptha P
authors.initials: JP
authors.lastname: Curtis
authors.affiliation: From Yale University School of Medicine, New Haven, CT (L.H.Y., C.M.V., J.P.C., S.E.I., A.M.L., D.L.J., S.E.P., W.N.K.); Denver VA Medical Center and University of Colorado School of Medicine (G.G.S., J.D.A.); Alpert Medical School of Brown University, Providence, RI (K.L.F., J.D.A.); Maine Medical Center, Portland (M.J.G.); National Institutes of Health/National Institute of Neurological Disorders and Stroke, Bethesda, MD (R.C.); University of Pennsylvania Perelman School of Medicine, Philadelphia (D.M.K.); and University of Rochester School of Medicine and Dentistry, NY (F.S.L.).
authors.forename: Silvio E
authors.initials: SE
authors.lastname: Inzucchi
authors.affiliation: From Yale University School of Medicine, New Haven, CT (L.H.Y., C.M.V., J.P.C., S.E.I., A.M.L., D.L.J., S.E.P., W.N.K.); Denver VA Medical Center and University of Colorado School of Medicine (G.G.S., J.D.A.); Alpert Medical School of Brown University, Providence, RI (K.L.F., J.D.A.); Maine Medical Center, Portland (M.J.G.); National Institutes of Health/National Institute of Neurological Disorders and Stroke, Bethesda, MD (R.C.); University of Pennsylvania Perelman School of Medicine, Philadelphia (D.M.K.); and University of Rochester School of Medicine and Dentistry, NY (F.S.L.).
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Schwartz
authors.affiliation: From Yale University School of Medicine, New Haven, CT (L.H.Y., C.M.V., J.P.C., S.E.I., A.M.L., D.L.J., S.E.P., W.N.K.); Denver VA Medical Center and University of Colorado School of Medicine (G.G.S., J.D.A.); Alpert Medical School of Brown University, Providence, RI (K.L.F., J.D.A.); Maine Medical Center, Portland (M.J.G.); National Institutes of Health/National Institute of Neurological Disorders and Stroke, Bethesda, MD (R.C.); University of Pennsylvania Perelman School of Medicine, Philadelphia (D.M.K.); and University of Rochester School of Medicine and Dentistry, NY (F.S.L.).
authors.forename: Anne M
authors.initials: AM
authors.lastname: Lovejoy
authors.affiliation: From Yale University School of Medicine, New Haven, CT (L.H.Y., C.M.V., J.P.C., S.E.I., A.M.L., D.L.J., S.E.P., W.N.K.); Denver VA Medical Center and University of Colorado School of Medicine (G.G.S., J.D.A.); Alpert Medical School of Brown University, Providence, RI (K.L.F., J.D.A.); Maine Medical Center, Portland (M.J.G.); National Institutes of Health/National Institute of Neurological Disorders and Stroke, Bethesda, MD (R.C.); University of Pennsylvania Perelman School of Medicine, Philadelphia (D.M.K.); and University of Rochester School of Medicine and Dentistry, NY (F.S.L.).
authors.forename: Karen L
authors.initials: KL
authors.lastname: Furie
authors.affiliation: From Yale University School of Medicine, New Haven, CT (L.H.Y., C.M.V., J.P.C., S.E.I., A.M.L., D.L.J., S.E.P., W.N.K.); Denver VA Medical Center and University of Colorado School of Medicine (G.G.S., J.D.A.); Alpert Medical School of Brown University, Providence, RI (K.L.F., J.D.A.); Maine Medical Center, Portland (M.J.G.); National Institutes of Health/National Institute of Neurological Disorders and Stroke, Bethesda, MD (R.C.); University of Pennsylvania Perelman School of Medicine, Philadelphia (D.M.K.); and University of Rochester School of Medicine and Dentistry, NY (F.S.L.).
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Gorman
authors.affiliation: From Yale University School of Medicine, New Haven, CT (L.H.Y., C.M.V., J.P.C., S.E.I., A.M.L., D.L.J., S.E.P., W.N.K.); Denver VA Medical Center and University of Colorado School of Medicine (G.G.S., J.D.A.); Alpert Medical School of Brown University, Providence, RI (K.L.F., J.D.A.); Maine Medical Center, Portland (M.J.G.); National Institutes of Health/National Institute of Neurological Disorders and Stroke, Bethesda, MD (R.C.); University of Pennsylvania Perelman School of Medicine, Philadelphia (D.M.K.); and University of Rochester School of Medicine and Dentistry, NY (F.S.L.).
authors.forename: Robin
authors.initials: R
authors.lastname: Conwit
authors.affiliation: From Yale University School of Medicine, New Haven, CT (L.H.Y., C.M.V., J.P.C., S.E.I., A.M.L., D.L.J., S.E.P., W.N.K.); Denver VA Medical Center and University of Colorado School of Medicine (G.G.S., J.D.A.); Alpert Medical School of Brown University, Providence, RI (K.L.F., J.D.A.); Maine Medical Center, Portland (M.J.G.); National Institutes of Health/National Institute of Neurological Disorders and Stroke, Bethesda, MD (R.C.); University of Pennsylvania Perelman School of Medicine, Philadelphia (D.M.K.); and University of Rochester School of Medicine and Dentistry, NY (F.S.L.).
authors.forename: J Dawn
authors.initials: JD
authors.lastname: Abbott
authors.affiliation: From Yale University School of Medicine, New Haven, CT (L.H.Y., C.M.V., J.P.C., S.E.I., A.M.L., D.L.J., S.E.P., W.N.K.); Denver VA Medical Center and University of Colorado School of Medicine (G.G.S., J.D.A.); Alpert Medical School of Brown University, Providence, RI (K.L.F., J.D.A.); Maine Medical Center, Portland (M.J.G.); National Institutes of Health/National Institute of Neurological Disorders and Stroke, Bethesda, MD (R.C.); University of Pennsylvania Perelman School of Medicine, Philadelphia (D.M.K.); and University of Rochester School of Medicine and Dentistry, NY (F.S.L.).
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Jacoby
authors.affiliation: From Yale University School of Medicine, New Haven, CT (L.H.Y., C.M.V., J.P.C., S.E.I., A.M.L., D.L.J., S.E.P., W.N.K.); Denver VA Medical Center and University of Colorado School of Medicine (G.G.S., J.D.A.); Alpert Medical School of Brown University, Providence, RI (K.L.F., J.D.A.); Maine Medical Center, Portland (M.J.G.); National Institutes of Health/National Institute of Neurological Disorders and Stroke, Bethesda, MD (R.C.); University of Pennsylvania Perelman School of Medicine, Philadelphia (D.M.K.); and University of Rochester School of Medicine and Dentistry, NY (F.S.L.).
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Kolansky
authors.affiliation: From Yale University School of Medicine, New Haven, CT (L.H.Y., C.M.V., J.P.C., S.E.I., A.M.L., D.L.J., S.E.P., W.N.K.); Denver VA Medical Center and University of Colorado School of Medicine (G.G.S., J.D.A.); Alpert Medical School of Brown University, Providence, RI (K.L.F., J.D.A.); Maine Medical Center, Portland (M.J.G.); National Institutes of Health/National Institute of Neurological Disorders and Stroke, Bethesda, MD (R.C.); University of Pennsylvania Perelman School of Medicine, Philadelphia (D.M.K.); and University of Rochester School of Medicine and Dentistry, NY (F.S.L.).
authors.forename: Steven E
authors.initials: SE
authors.lastname: Pfau
authors.affiliation: From Yale University School of Medicine, New Haven, CT (L.H.Y., C.M.V., J.P.C., S.E.I., A.M.L., D.L.J., S.E.P., W.N.K.); Denver VA Medical Center and University of Colorado School of Medicine (G.G.S., J.D.A.); Alpert Medical School of Brown University, Providence, RI (K.L.F., J.D.A.); Maine Medical Center, Portland (M.J.G.); National Institutes of Health/National Institute of Neurological Disorders and Stroke, Bethesda, MD (R.C.); University of Pennsylvania Perelman School of Medicine, Philadelphia (D.M.K.); and University of Rochester School of Medicine and Dentistry, NY (F.S.L.).
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Ling
authors.affiliation: From Yale University School of Medicine, New Haven, CT (L.H.Y., C.M.V., J.P.C., S.E.I., A.M.L., D.L.J., S.E.P., W.N.K.); Denver VA Medical Center and University of Colorado School of Medicine (G.G.S., J.D.A.); Alpert Medical School of Brown University, Providence, RI (K.L.F., J.D.A.); Maine Medical Center, Portland (M.J.G.); National Institutes of Health/National Institute of Neurological Disorders and Stroke, Bethesda, MD (R.C.); University of Pennsylvania Perelman School of Medicine, Philadelphia (D.M.K.); and University of Rochester School of Medicine and Dentistry, NY (F.S.L.).
authors.forename: Walter N
authors.initials: WN
authors.lastname: Kernan
mesh_terms: D054058:Acute Coronary Syndrome / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D000368:Aged; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007333:Insulin Resistance / Q000502:physiology*; D038622:Internationality; D002546:Ischemic Attack, Transient / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D000077205:Pioglitazone; D020521:Stroke / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D045162:Thiazolidinediones / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077205:Pioglitazone
keywords: insulin resistance; ischemic attack, transient; myocardial infarction; pioglitazone; stroke