Samuel Z. Goldhaber, MD


December 17, 2013

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Hello. This is Dr. Sam Goldhaber for the Clot Blog at on Medscape, speaking to you from the American Heart Association (AHA) scientific sessions in Dallas. Today I am going to speak about the COAG trial, an National Institutes of Health-sponsored trial that aimed to optimize warfarin anticoagulation by using pharmacogenetic information to improve the dosing.

The COAG trial was unveiled at the AHA meeting and simultaneously published in the New England Journal of Medicine.[1] The trial included about 1000 patients who were newly prescribed warfarin. They were randomly assigned to 1 of 2 strategies: (1) either a novel pharmacogenetic strategy, which incorporated rapid-turnaround genetic testing of genes that predict the way warfarin will be metabolized, plus relevant clinical information, or (2) a control group where relevant clinical information such as age, gender, weight, comorbid conditions, and important concomitant medications were taken into account. These different strategies were compared.

It was not a clinical endpoint trial but rather a surrogate endpoint trial. And the surrogate endpoint was the time that the patient stays within the therapeutic range (TTR) between INR 2.0 and 3.0. The hypothesis was that pharmacogenetic information would afford much more precision of the initial dosing of warfarin. This trial tested this warfarin dosing strategy for the first 5 days of warfarin therapy and then assessed the TTR for about 1 month.

For the pharmacogenetic strategy, blood was obtained and rapidly turned around with genetic results so that an algorithm that incorporates pharmacogenetic information could be compared with an algorithm that only has the relevant clinical information.

Surprise of surprises, there was absolutely no improvement in the time within the therapeutic range in the patients who were randomly assigned to a dosing strategy based on pharmacogenetic testing and clinical information compared with those dosed according to clinical information only. The time within the therapeutic range in both groups was 45% in the first 30 days. And these were patients who are being watched like hawks as part of this clinical trial. We usually think of an acceptable time within the therapeutic range of being at least 60%. This was 45%. Now, the 60% number is usually based on a much longer time period than the first month, because the first month includes the beginning of warfarin initiation when nobody is in the therapeutic range.

But I think it's rather humbling to find a TTR of 45% at 30 days after initiating warfarin, and it is disappointing that adding the genetic information in this larger definitive COAG trial did not ultimately improve the time within the therapeutic range despite some very promising smaller studies.

I don't think there is any evidence at the moment for us to incorporate pharmacogenetic testing into our routine clinical practice when we are initiating warfarin in our patients. We should just stick with the clinical information since that seems to do just as good of a job. This trial is very important because this may save many hundreds of millions of dollars that might otherwise have been spent on routinely obtaining genetic information.

So it's an important negative trial, and I think it's particularly important that it is presented now in the context of the new information that we have with the novel oral anticoagulant, where we can rest assured that almost all of the patients are fully and effectively anticoagulated within several hours of taking their first pill or capsule of a novel oral anticoagulant.

This is Dr. Sam Goldhaber, signing off for the Clot Blog.


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