Tag Archives: glaxo

Avandia has a moderate-to-very-large practical effect on heart failure

Home, P.D., et al. Rosiglitazone evaluated for cardiovascular outcomes — an interim analysis. The New England Journal of Medicine. 5 June 2007. Available online:http://content.nejm.org/cgi/content/full/NEJMoa073394 (via Medical News Today).

Avandia is a drug designed to treat Type II Diabetes. Type 2 Diabetes leads to heart attack, death, and a lot of other bad things. A safe drug that treats it would be very good. Many people think that Avandia (rosiglitazone maleate) is that drug. However, a recent article in The New England Journal of Medicine reported that Avandia has a large-to-very-large effect on patient death. Because this is important news, a new article was rushed to the New England Journal that reported results-so-far of a study that’s not completed.

The results section is statistics-y:

Because the mean follow-up was only 3.75 years, our interim analysis had limited statistical power to detect treatment differences. A total of 217 patients in the rosiglitazone group and 202 patients in the control group had the adjudicated primary end point (hazard ratio, 1.08; 95% confidence interval [CI], 0.89 to 1.31). After the inclusion of end points pending adjudication, the hazard ratio was 1.11 (95% CI, 0.93 to 1.32). There were no statistically significant differences between the rosiglitazone group and the control group regarding myocardial infarction and death from cardiovascular causes or any cause. There were more patients with heart failure in the rosiglitazone group than in the control group (hazard ratio, 2.15; 95% CI, 1.30 to 3.57).

Several results are reported here. The most important to consider are practical signifiance and statistical significance . From my statistics notes:

Statistical significance is concerned with whether an observed mean difference could likely be due to sampling error
Practical significance is concerned with whether an observed effect is large enough to be useful in the real world

For instance, imagine that you wish to be more productive, so you buy a new computer . You notice that you get twice as much done in an hour with the computer than without it. The practical significance would be very large (double!). However, you didn’t look at enough people to reject the notion that maybe it was just a fluke. So there would not be statistical significance.

A similar thing happened in this study. The last part of the quoted paragraph (“hazard ratio, 2.15”) means that, practically speaking, for every heart attack for diabetes type 2 patients who aren’t taking Avandia, patients taking Avandia have 2.15 heart attacks. However, the study did not meet statistical significance — the new research did not look at enough people to say whether or not this very large practical effect was due to chance or not.

A problem with the study — that the authors note — is that they are reporting their results too soon. (They are doing this because there is talk of forcing Avandia off the market, which would effect all patients who currently take Avandia and obviously hurt GlaxoSmithKline, the company that makes it.) I have heard anecdotes that one of the side-effects of Avandia is “preamature-aging.” If this is true, the negative effects of Avandia would get worse and worse over time. Thus, future research may go from the current two (where all find practical significance, but only one finds statistical significance) to a situation where all find statistical significance.

A "Large" to "Very Large" Effect Size

Those who have been reading tdaxp over the past few months will know why this story is personal.

My first reaction is that the 43% higher risk of heart attacks

Pooled results of dozens of studies on nearly 28,000 people revealed a 43 percent higher risk of heart attack for those taking Avandia compared to people taking other diabetes drugs or no diabetes medication, according to the analysis published online Monday. The study, published by the New England Journal of Medicine, also found a trend toward more heart-related deaths.

Presumably means that .30 of the variation in heart attacks is explained by taking Avandia. This is a “large effect size.” It should show up in smaller sized studies. Unless the most recent study is an outlier, it’s strange that the effect has not been seen before.

Among worst cases, the increased risk is 64% (presumably, .38 of the variation is explained by taking Avandia). And indeed, apparently the FDA has known about this since 2002:

In 2002, U.S. Food and Drug Administration staff scientists called for reports of congestive heart failure to be included on the label of Avandia as well as Actos, made by Takeda Pharmaceutical Co. Ltd., the group said, citing an internal FDA document.

The group released the memo one day after researchers reported Avandia, or rosiglitazone, raises the risk of cardiovascular-related death by 64 percent and the risk of heart attack by 43 percent.

To me, though, blaming the FDA is like blaming the traffic police for a hit-and-run.

Glaxo strongly objected to the results and defended use of the drug, which treats type 2 diabetes.

I imagine I’ll be following this for a while.