Angela Aziz Donnelly April 5, 2016 Journal Club Angela Aziz Donnelly April 5, 2016

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

Insulin Resistance Intervention after Stroke 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 IRIS: To determine the effectiveness of pioglitazone for reducing the risk for stroke or MI among patients who have had a recent ischemic stroke and also have insulin resistance

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 Treatment of insulin resistance has potential to benefit a large number of patients – SIRS I study estimated that about 50% of non-diabetic stroke patients had insulin resistance

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) Mechanism by which insulin resistance increases risk for vascular disease is likely multi-factorial - associations between insulin resistance and endothelial dysfunction, inflammation, dyslipidemia, hypertension, abnormal fibrinolysis, and atherogenesis Of the various strategies, TZDs were determined to be the most practical with the most profound effects. Pioglitazone was then chosen because it has once daily dosing and appeared to have a more favorable effect on plasma lipids

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 Funded by the National Institute of Neurological Disorders and Stroke, who appointed an independent data and safety monitoring board to conduct interim analyses Qualifying stroke – Focal neuro deficit that is attributable to brain ischemia Deficit must persist for over 24 hours or be associated with new sign of ischemia on CT/MR In cases of deficits that last over 24 hours associated with a CT or MR scan that does NOT show an infarction, the imaging must document the absence of a hemorrhage or other non-ischemic pathology Excluded strokes: - Cardioembolic strokes - Due to the thought that the pathophysiology of cardioembolic strokes was not associated with insulin resistance - Strokes related to head trauma, dissection, or medical instrumentation Insulin resistance – Defined as more than a 3.0 on the HOMA-IR index. The index threshold of 3 was chosen because it identifies the highest quartile among patients without diabetes HOMA- IR calculated by (fasting glucose * fasting insulin)/22.5 A score of 1.0 or below indicates insulin-sensitivity (healthy or optimal). A score above 1.9 indicates early insulin resistance, and a score above 2.9 shows significant insulin resistance

Research Methodology Exclusion criteria Temporary Exclusion 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 Heart failure: Class II – Comfortable at rest. Ordinary physical activity causes fatigue, palpitations, or dyspnea. Need to have EF > 40% Class III – Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitations, or dyspnea Class IV – Unable to carry on and physical activity without discomfort. Symptoms of HF at rest Additional restrictions added during the trial: History of HF, Bladder cancer, or certain conditions that increased the risk of bladder cancer Temporary exclusion – If ALT over 2.5 times the upper limit of normal or Hgb less than 8.5, participant was temporarily ineligible, but could undergo repeat testing

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 Patient’s individual primary care doctors had direct responsibility for providing best current medical care for risk factor modification. However, IRIS investigators assisted PCPs by monitoring risk factors, and informing PCPs and patients of the results. Recommendations were based on national guidelines

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

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

Patients from 167 centers in 7 different countries

Alleged irregularity in the informed consent process at one institution resulted in 19 patients being removed from the study

The two study groups had similar characteristics at baseline The mean age was 63.5 in both groups The index event was stroke in 88% of the pioglitazone group and 87% in the placebo group Similar comorbidities– HTN – 71% the pioglitazone group, 72% in the placebo group CAD – 12% in pioglitazone group, 11% in placebo group A fib – 7% in pioglitazone group, 7% in placebo group

Levels of insulin resistance as measured by the HOMA-IR index were not different at baseline (4.7 and 4.6 respectively) Concomitant medications – including statins, anti-platelets, anticoagulation, and blood pressure medications were about the same at baseline

Types of stroke were similar at baseline, with most strokes being lacunar, large vessel, or uncertain Majority of strokes in anterior circulation Majority of patients with mRS 0 or 1 in both groups Most patients with NIHSS <5

Patients in two groups had similar rates of adherence to recommended practices for secondary prevention

Findings

Primary Outcome– At the end of the study, 9.0% of patients in the pioglitazone group and 11.8% of patients in the placebo group had a stroke or MI, which was a statistically significant difference. Absolute risk reduction of 2.8 percent, and relative risk reduction of 24% (eg. patient’s in pioglitazone group were 24% less likely to have a stroke or MI at 5 years.) NNT 35  Treating 100 patients with pioglitazone for 5 years will prevent ~3 from having a recurrent stroke/MI (ARR = 11.8-9.0 = 2.8%. NNT = Inverse of ARR)

Secondary Outcome – The only secondary outcome that was statistically significant was the rate of progression to diabetes

Patients in the pioglitazone group had more weight gain, edema, SOB, and bone fractures than did patients in the placebo group Number needed to harm for serious bone fracture 52  Treating 100 patients with pioglitazone for 5 years will cause ~2 patients to suffer a serious bone fracture

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) Strengths

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 Weaknesses

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