Heart Failure After Ischemic Stroke or TIA in Insulin-Resistant Patients Without Diabetes Treated with Pioglitazone
Background—The Insulin Resistance Intervention after Stroke (IRIS) trial demonstrated that pioglitazone reduced risk for both cardiovascular events and diabetes in insulin resistant patients. However, concern remains that pioglitazone may increase risk for heart failure (HF) in susceptible individuals.
Methods—In IRIS, patients with insulin resistance but without diabetes were randomized to pioglitazone or placebo (1:1) within 180 days of an ischemic stroke or TIA and followed for up to 5 years. To identify patients at higher HF risk with pioglitazone we performed a secondary analysis of IRIS participants without HF history at entry. HF episodes were adjudicated by an external review and treatment effects were analyzed using time-to-event methods. A baseline HF risk score was constructed from a Cox model estimated using stepwise selection. Baseline patient features (individually and summarized in risk score) and post-randomization events were examined as possible modifiers of the effect of pioglitazone. Net cardiovascular benefit was estimated for the composite of stroke, myocardial infarction (MI) and hospitalized HF.
Results—Among 3851 patients, mean age was 63 years and 65% were male. The 5-year HF risk did not differ by treatment (4.1% pioglitazone; 4.2% placebo). Risk for hospitalized HF was low and not significantly greater in pioglitazone compared to placebo groups (2.9% vs. 2.3%, p=0.36). Older age, atrial fibrillation, hypertension, obesity, edema, high C-reactive protein, and smoking were risk factors for HF. However, the effect of pioglitazone did not differ across levels of baseline HF risk (hazard ratio [95% confidence interval] for pioglitazone vs. placebo for patients at low, moderate and high risk: 1.03 [0.61, 1.73], 1.10 [0.56, 2.15], 1.08 [0.58, 2.01]; interaction p-value, 0.98). HF risk was increased in patients with vs. those without incident MI in both groups (pioglitazone: 31.4% vs. 2.7%; placebo: 25.7% vs. 2.4%, p<0.0001). Edema, dyspnea and weight gain in the trial did not predict HF hospitalization, but led to more study drug dose reduction with a lower mean dose of pioglitazone vs. placebo (29±17 mg vs. 33±15 mg; p<0.0001). Pioglitazone reduced the composite outcome of stroke, MI or hospitalized HF (HR, 0.78; p=0.007).
Conclusions—In IRIS, with surveillance and dose adjustments, pioglitazone did not increase risk of HF, and conferred net cardiovascular benefit in patients with insulin resistance and cerebrovascular disease. The risk of HF with pioglitazone was not modified by baseline HF risk. The IRIS experience may be instructive for maximizing the net benefit of this therapy.
Clinical Trial Registration—URL: www.clinicaltrials.gov Unique identifier: NCT00091949
- Received March 8, 2018.
- Revision received May 31, 2018.
- Accepted June 11, 2018.