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Journal Club

This journal club review analyzes the impact of pioglitazone on reducing stroke and myocardial infarction rates in patients with insulin resistance post-stroke or TIA based on a 5-year clinical trial. The study design, outcomes, and implications for clinical practice are discussed.

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Journal Club

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Presentation Transcript

  1. Journal Club Angela Aziz Donnelly April 5, 2016

  2. Pioglitazone After Ischemic Stroke or Transient Ischemic Attack NEJM Feb 17, 2016

  3. Hypothesis: Pioglitazone would reduce the rates of stroke and myocardial infarction after ischemic stroke or TIA in select patients IRIS Insulin Resistance Intervention after Stroke

  4. Background • Patients affected by stroke and TIA are at risk for another event • Current treatment for secondary stroke prevention is fairly limited • Explores insulin resistance as a possible new treatment target

  5. Background • Many proposed mechanisms for why the presence of insulin resistance increases risk for vascular disease • There are various strategies to improve insulin sensitivity – including lifestyle modification, TZDs, and other medications (eg. metformin)

  6. Research methodology • International, randomized, double-blind, placebo-controlled clinical trial • Eligible Patients: Men and Women at least 40 years of age who had a qualifying ischemic stroke or TIA during the previous 6 months AND met criteria for insulin resistance

  7. Research Methodology • Exclusion criteria • Patients with diabetes • Patients with class 3 or 4 heart failure, or patients with class 2 heart failure with reduced EF • Pregnancy • Moderate/severe pitting edema • Carotid revascularization within 14 days • Use of an estrogen-containing contraceptive or oral glucocorticoid • Temporary Exclusion • Abnormal liver function • Severe anemia

  8. Research Methodology • Patients then randomly assigned in a 1:1 ratio to receive either pioglitazone or matching placebo • Pioglitazone was titrated from an initial dose of 15 mg to a final dose of 45 mg if no side effects encountered • If patient’s had side effects, they were treated according to algorithms • Adherence was monitored by asking about drug use and performing pill counts • Patient’s individual primary care doctors had direct responsibility for providing best current medical care for risk factor modification

  9. Trial Outcomes Primary outcome • First fatal or nonfatal stroke or fatal or nonfatal MI Secondary outcomes • Recurrent stroke • Acute MI or unstable angina • The composite of stroke, MI, or HF resulting in hospitalization or death • All-cause mortality • Progression to overt diabetes • Cognitive decline from baseline

  10. Statistical Analysis • Analyses performed on an intention-to-treat basis • The primary outcome and all secondary outcomes (except cognitive function) were analyzed by means of the time-to-first-event method

  11. Findings

  12. Conclusion • Good study design • Multi-center • Double-blind • Randomized controlled trial • Large sample size • 5 years • Groups similar at baseline with similar control of comorbidities between groups • Included the patients that would benefit the most from additional secondary stroke prevention (Low NIHSS/mRS)

  13. Conclusion • Strict inclusion/exclusion criteria – eg. No diabetes, no heart failure • Majority of population was white, male • Used HOMA-IR for measuring insulin resistance – how would we do this in clinical practice • No comparison to lifestyle modifications

  14. Discussion/implications • Can we apply this study to our current patient population? • Given risks versus benefits, would you use this in clinical practice? • Impressive NNT of 35. How does this compare to our current standard of care, eg. treatment with high intensity statin

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