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Original Investigation
September 18, 2017

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

Author Affiliations
  • 1Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut
  • 2Department of Neurology, Yale School of Medicine, New Haven, Connecticut
  • 3Predictive Analytics and Comparative Effectiveness Center, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, Massachusetts
  • 4National Institute of Neurological Disorders and Stroke, Bethesda, Maryland
  • 5Department of Neurological Sciences, University of Nebraska Medical School, Omaha
  • 6Department of Neurology, Alpert Medical School of Brown University, Providence, Rhode Island
  • 7Maine Medical Center, Portland
  • 8Statistical Center for HIV/AIDS Research Prevention, Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 9University of Connecticut School of Medicine, Farmington
JAMA Neurol. Published online September 18, 2017. doi:10.1001/jamaneurol.2017.2136
Key Points

Question  After an ischemic stroke or transient ischemic attack, do patients at higher risk for recurrent stroke or myocardial infarction derive more benefit from pioglitazone hydrochloride compared with patients at lower risk?

Findings  In this double-blind, placebo-controlled trial, the absolute risk reduction for recurrent stroke or myocardial infarction was larger for patients at higher risk of recurrent stroke or myocardial infarction compared with those at lower risk (4.9% vs 1.9%). The relative risk reduction, however, was similar, and neither difference reached statistical significance.

Meaning  Patients at higher risk for stroke or myocardial infarction may derive a greater absolute benefit from pioglitazone.

Abstract

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

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