IRIS: New Analysis Finds Best Candidates for Pioglitazone After Stroke

Megan Brooks

September 26, 2017

A planned secondary analysis of the Insulin Resistance Intervention After Stroke (IRIS) study helps to identify patients who are most likely to benefit from treatment with pioglitazone (Actos, Takeda Pharmaceuticals) after ischemic stroke or transient ischemic attack (TIA).

"Those who benefit most, not surprisingly, are those who start out with the highest pretreatment risk for stroke or MI [myocardial infarction]," Walter Kernan, MD, from Yale School of Medicine, New Haven, Connecticut, told Medscape Medical News.

"Our findings can be used by clinicians in shared decision making with patients, to help patients make a choice for or against use of pioglitazone that is consistent with their preference and values and informed by data," Dr Kernan said.

The study was published online September 18 in JAMA Neurology.

Best Candidates for Pioglitazone

Results of the IRIS trial were published last year in the New England Journal of Medicine to coincide with presentation by Dr Kernan at the International Stroke Conference (ISC) 2016.

As previously reported by Medscape Medical News, in patients with recent ischemic stroke or TIA and insulin resistance, pioglitazone reduced recurrent stroke or MI by about one fourth compared with placebo (pioglitazone, 9.0% vs placebo, 11.8%; hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.62 - 0.93). 

Pioglitazone was also associated with less new diabetes vs placebo (3.8% vs 7.7%) but more weight gain above 4.5 kg (52.2% vs 33.7%), more peripheral edema (35.6% vs 24.9%), and more bone fracture (5.1% vs 3.2%).

Dr Kernan and colleagues concluded that pioglitazone treatment in 100 patients similar to those in this trial for about 5 years would prevent 3 patients from having a stroke or MI, but bone fractures requiring surgery would be expected to occur in 2 patients.

They further concluded that it seems "reasonable to consider individual treatment preference and risk of drug-related adverse events in addition to potential benefits when making patient-specific decisions regarding therapy."

The goal of the planned secondary analysis was to identify which patients with stroke and insulin resistance are most likely to benefit from pioglitazone treatment. To do this, the researchers divided the IRIS trial population into two subpopulations of equal size with a high (above the median, 17.2%) or low (below the median, 6.9%) 5-year risk for stroke or MI, based on baseline patient characteristics.

In this analysis, the 5-year risk for stroke or MI in the lower baseline risk group was 6.0% with pioglitazone vs 7.9% with placebo. In the higher baseline risk group, the 5-year risk for stroke or MI was 14.7% with pioglitazone compared with 19.6% with placebo. The relative risk reduction for stroke or MI with pioglitazone was similar in the high and low pretreatment risk groups (HR, 0.75 vs 0.77; P = .92).

However, because of "effective risk stratification and stable relative risk reduction across risk groups, the absolute risk reduction was substantially larger (4.9%) for patients at high pretreatment risk compared with those at low pretreatment risk (1.9%)," Dr Kernan and colleagues report. 

They calculate that 21 high-risk patients would need to be treated for roughly 5 years to prevent one stroke or MI compared with 53 low-risk patients.

Patients with high pretreatment risk had lower rates of weight gain, defined as greater than 10% increase from baseline with pioglitazone (31.5% vs 15.8% with placebo) than patients with low pretreatment risk (37.1% with pioglitazone vs 19.0% with placebo).

However, high-risk patients also had higher rates of bone fracture with pioglitazone (16.9% vs 10.1% with placebo) relative to low-risk patients (10.6% vs 7.4% with placebo).

Summing up, Dr Kernan and colleagues say this analysis shows that patients at higher baseline risk derive greater benefit from pioglitazone in terms of prevention of stroke and MI but also experience a higher absolute risk for bone fracture compared with patients at lower baseline risk.

They point out that this analysis was not designed to yield recommendations for prescribing pioglitazone.

"However, our findings may help clinicians talk with patients who are considering pioglitazone therapy after ischemic stroke or TIA. In particular, clinicians can use these findings to more precisely estimate the likelihood for specific absolute benefits and harms, allowing patients to make informed decisions based on the personal values they assign to prevention of vascular events vs risk for adverse events," they write.

Risk-Adapted Approach

In an editorial published with the study, Graeme Hankey, MD, from the Department of Neurology, The University of Western Australia in Perth, says the IRIS trial investigators are to be "congratulated for undertaking this thoughtful and thorough analysis."  

The results, writes Dr Hankey, will "encourage clinicians to adopt a risk-adapted approach to patient management based on the prognostic factor profile of the patient, which will aid clinicians and patients in their decision to begin long-term pioglitazone therapy."

In his view, "The patients with perhaps the highest benefit to harm ratio for pioglitazone are those 70 to 79 years of age with a history of coronary artery disease and/or hypertension and/or current smoking, although current smokers will be encouraged to stop smoking as their first priority before considering pioglitazone therapy."

"Although very elderly individuals (≥80 years of age) have arguably the highest risk of stroke and MI, and the most to gain from pioglitazone therapy, they also have the highest risk of bone fracture. The relative importance that these patients attribute to their risks of stroke and MI vs bone fracture will likely determine their preference for long-term pioglitazone therapy," Dr Hankey concludes.

The study was funded by the National Institute of Neurological Disorders and Stroke/National Institutes of Health. Dr Kernan and Dr Hankey have disclosed no relevant financial relationships.

JAMA Neurol. Published online September 18, 2017. Abstract, Editorial

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