Clinical Health Updates

Rosiglitazone (Avandia) associated with increased risk of acute MI

Clinical Question:
Does rosiglitazone (Avandia) increase the risk of adverse cardiovascular events?

Bottom Line:
This study acquainted us with an evidence that short-term use of rosiglitazone may increase the risk of Myocardial Infarction and cardiovascular death. While the absolute possibilty was small, the goal of diabetes treatment is to decrease cardiovascular disease, the largest cause of death in patients with diabetes. Longer and larger studies using cardiovascular outcomes as a prespecified outcome and meta-analysis using individual patient level data are needed to more definitively answer this question. A study of pioglitazone (Actos) found no increase in cardiovascular events but did show an increase in hopsitalizations for heart failure. Aggressive attention to cardiovascular risk factors remains the most important thing we can do for our diabetic patients.

Reference:
Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356: epub.

Study Design:
Meta-analysis (randomized controlled trials)

Synopsis:
The thiazolinediones family have a patterned history: troglitazone caused hepatotoxicity and was removed from the market, while muraglitazar never made it to market because it increased the risk of cardiovasculr events and myocardial infarction (MI). Rosiglitazone, though, was thought to be safe based on the results of short, small studies submitted to the FDA. However, these studies were designed to detect changes in blood sugar, and not to detect changes in cardiovascular mortality, MI, or all-cause mortality. The authors of this meta-analysis have therefore pooled data from 42 smaller trials to determine if use of the drug increases the risk of MI or cardiovascular death. Since the studies were not specifically designed to evaluate cardiac outcomes, most did not describe how cardiac endpoints were determined. Most studies were between 24 and 52 weeks duration, with a typical dosage range for rosiglitazone of 4 to 8 mg per day. The average age of patients was 56 years and over half were men; the mean hemoglobin A1C was 8.2%.

The results showed a significant increase in the likelihood of MI (odds ratio 1.43, 95% CI 1.03 to 1.98) and a borderline increase in the risk of death from cardiovascular causes (OR 1.64, 95% CI 0.98 – 2.74). The absolute increase in risk of MI was small, approximately 0.4%. On the other hand, the studies were short and most excluded patients with pre-existing heart disease, which explains the small total number of cardiovascular events in both groups. Results were similar whether the control group took placebo or an active comparator, although the number of patients in each comparator group were relatively small. The authors used a fixed effects model to combine the studies; a more conservative approach would have been to use a random effects model, which may not have shown a significant difference in outcomes.