Clinical Question

Are peroxisome proliferator–activated receptor (PPAR) gamma agonists effective at preventing recurrent stroke and other serious vascular events in people with previous stroke or transient ischemic attack (TIA)?

Evidence-Based Answer

PPAR gamma agonists are probably effective in preventing recurrent stroke in people with previous stroke or TIA (absolute risk reduction [ARR] = 2.9%; 95% CI, 0.1% to 4.8%; number needed to treat [NNT] = 35; 95% CI, 21 to 1,000). (Strength of Recommendation [SOR]: B, based on inconsistent or limited-quality patient-oriented evidence.) PPAR gamma agonists also appear to be effective in preventing other serious vascular events (relative risk = 0.73; 95% CI, 0.54 to 0.99). (SOR: B, based on inconsistent or limited-quality patient-oriented evidence.) It is uncertain whether adverse effects are more common in those treated with PPAR gamma agonists vs. placebo.¹

Practice Pointers

Cerebrovascular accidents, or strokes, are classified as ischemic (80%) or hemorrhagic. Stroke recurs in 30% of cases.¹ People who have a recurrent stroke have more than double the cumulative mortality rate vs. those with only a single episode of stroke.² Diabetes mellitus contributes to one in nine cases of stroke and TIA.³ PPAR gamma agonists are insulin-sensitizing drugs used to treat hyperglycemia with insulin resistance and have been widely recommended for the treatment of type 2 diabetes.

This Cochrane review is an update of an initial review performed in January 2014. Five RCTs with 5,039 participants were identified; four evaluated pioglitazone (Actos) and one evaluated rosiglitazone (Avandia).¹ Three studies that included participants with recurrent stroke from the United States, Japan, and South Africa were ultimately included. They revealed that PPAR gamma agonists probably reduced the recurrence of stroke compared with placebo (ARR = 2.9%; 95% CI, 0.1% to 4.8%; NNT = 35; 95% CI, 21 to 1,000; 4,979 participants). The risk of bias was unclear because of the lack of information on randomization in one study, and a single large study with 3,876 participants influenced the outcome.

Common adverse effects associated with the use of PPAR gamma agonists include edema, anemia, liver dysfunction, and heart failure. In a 2010 trial, an increased risk of mortality and vascular events was found with rosiglitazone compared with pioglitazone in people with diabetes who were older than 65 years.⁴ In the current review, the authors did not demonstrate that adverse effects occurred more often in participants treated with PPAR gamma agonists vs. placebo because of a wide CI and a high level of statistical heterogeneity. One study demonstrated that PPAR gamma agonists were associated with fewer serious vascular events, but there was a high risk of bias because of incomplete outcomes data. Data from this study were not part of the meta-analysis. Disability caused by vascular events or quality-of-life changes were not reported in any of the studies.

This is the first review of its kind; no other review articles have yet been published. PPAR gamma agonists are not considered first-line therapy, but they may be considered in combination with other therapy in patients with no compelling need to minimize hypoglycemia or if cost is a major issue. In patients who are at high risk for or have established atherosclerotic cardiovascular disease, chronic kidney disease, or heart failure, PPAR gamma agonists may be considered.⁵ Because of the small number of included studies and level of quality of some of the studies, the conclusions of this review should be interpreted with caution.

The practice recommendations in this activity are available at http://www.cochrane.org/CD010693.

Editor's Note: The ARR, NNT, and related CIs reported in this Cochrane for Clinicians were calculated by the authors based on raw data provided in the original Cochrane review.