Saturday, September 15, 2007

Idraparinux, the van Gogh investigators, and clinical trials pointillism: connecting the dots shows that Idraparinux increases the risk of death

It eludes me why the NEJM continues to publish specious, industry-sponsored, negative, non-inferiority trials. Perhaps they do it for my entertainment. And this past week, entertained I was indeed.

Idraparinux is yet another drug looking for an indication. Keep looking, Sanofi. Your pipeline problems will not be solved by this one.

First, let me dismiss the second article out of hand: it is not fair to test idraparinux against placebo (for the love of Joseph!) for the secondary prevention of VTE after a recent epidode! (

It is old news that one can reduce the recurrence of VTE after a recent episode by either using low intensity warfarin ( or by extending the duration of warfarin anticoagulation ( Therefore, the second van Gogh study does not merit further consideration, especially given the higher rate of bleeding in this study.

Now for the first study and its omissions and distortions. It is important to bear in mind that the only outcome that cannot be associated with ascertainment bias (assuming a high follow-up rate) is mortality, AND that the ascertainment of DVT and PE are fraught with numerous difficulties and potential biases.

The Omission: Failure to report in the abstract that Idraparinux use was associated with an increased risk of death in these studies, which was significant in the PE study, and which trended strongly in the DVT study. The authors attempt to explain this away by suggesting that the increased death rate was due to cancer, but of course we are not told how causes of death were ascertained (a notoriously difficult and messy task), and cancer is associated with DVT/PE which is among the final common pathways of death from cancer. This alone, this minor factoid that Idraparinux was associated with an increased risk of death should doom this drug and should be the main headline related to these studies.

Appropriate headline: "Idraparinux increases the risk of death in patients with PE and possibly DVT."

If we combine the deaths in the DVT and PE studies, we see that the 6-month death rates are 3.4% in the placebo group and 4.5% in the idraparinux group, with an overall (chi-square) p-value of 0.035 - significant!

This is especially worrisome from a generalizability perspective - if this drug were approved and the distinction between DVT and PE is blurred in clinical practice as it often is, we would have no way of being confident that we're using it in a DVT patient rather than a PE patient. Who wants such a messy drug?

The Obfuscations and Distortions: Where to begin? First of all, no justification of an Odds Ratio of 2.0 as a delta for non-inferiority is given. Is twice the odds of recurrent DVT/PE insignificant? It is not. This Odds Ratio is too high. Shame.

To give credit where it is due, the investigation at least used a one sided 0.025 alpha for the non-inferiority comparison.

Second, regarding the DVT study, many if not the majority of patients with DVT also have PE, even if it is subclinical. Given that ascertainment of events (other than death) in this study relied on symptoms and was poorly described, that patients with DVT were not routinely tested for PE in the absence of symptoms, and that the risk of death was increased with idraparinux in the PE study, one is led to an obvious hypothesis: that the trend towary an increased risk of death in the DVT study patients who received idraparinux was due to unrecognized PE in some of these patients. The first part of the conclusion in the abstract "in patients with DVT, once weekly SQ idraparinux for 3 or 6 months had an efficacy similar to that of heparin and vitamin K antagonists" obfuscates and conceals this worrisome possibility. Many patients with DVT probably also had undiagnosed PE and might have been more likely to die given the drug's failure to prevent recurrences in the PE study. The increased risk of death in the DVT study might have been simply muted and diluted by the lower frequency of PE in the patients in the DVT study.

Then there is the annoying the inability to reverse the effects of this drug with a very long half-life.

Scientific objectivity and patient safety mandate that this drug not receive further consideration for clinical use. Persistence with the study of this drug will most likely represent "sunk cost bias" on the part of the manufacturer. It's time to cut bait and save patients in the process.

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