Dabigatran: is laboratory monitoring really unnecessary?

April 4, 2012, 3:10 pm

★★★½☆

Impact of dabigatran on a large panel of routine or specific coagulation assays. Douxfils J et al. Thromb Haemost 2012 Mar 22;107(5). [Epub ahead of print]

Abstract

When the direct thrombin inhibitor dabigatran (Pradaxa) was first approved by the FDA in October 2010 for the prevention of strokes in patients with non-valvular atrial fibrillation, the touted advantage of the drug over coumadin was that predictable pharmacokinetics would eliminate the need for frequent blood tests to monitor the level of anticoagulation. This advantage was presumed to outweigh the known disadvantages of the drug: there were actually no laboratory tests known to accurately reflect anticoagulation level, and there was no antidote that could reverse the effects of dabigatran in cases of overdose or hemorrhage.

In the last year and a half, as the medical community acquired more experience with dabigatran as a result of post-marketing surveys and reports, hematologists and coagulation specialists have begun to re-evaluate the safety of using the drug without laboratory monitoring. Last December, the FDA announced that it was investigating reports of serious bleeding in patients taking dabigatran. Between March 2008 and October 2011, there were 260 cases of fatal hemorrhage reported in these patients.

The paper by Douxfils et al is a laboratory study using blood and plasma spiked with various concentrations of dabigatran, whose goal was to determine which assays best measured the pharmacodynamic effects of dabigatran. We’ll get to the conclusions in a minute. But I found the most interesting parts of the paper to be observations the authors make in passing that might be surprising to some clinicians. (They were to me):

. . . the difficult pharmacokinetic characteristics of dabigatran, the concentration-effect relationship and the bleeding risks strongly suggest that drug monitoring may be recommended.

This seems to contradict the original contention that reliable pharmacokinetics made monitoring of dabigatran unnecessary.

. . . drug monitoring [of dabigatran] remains under passionate debate and even if it is not recommended by the marketing authorization holder, it is strongly suggested by different authors.

The following situations might require laboratory control for patient management: patients presenting in emergency with adverse events (thrombosis or hemorrhage), necessity of immediate reversal of anticoagulation, renal failure, liver failure, suspicion or known interaction with other drugs and bridging.

An inter-individual variability [among patients taking dabigatran] is also mentioned in the study confirming the hypothesis that monitoring may be valuable to minimize the risk of the product.

As for this study, the authors found that activated partial thromboplastin time  (aPTT) could be “used as a screening test to exclude a bleeding risk associated with DE [dabigatran] administration.” This test is reliably elevated by dabigatran, but becomes non-linear at high levels and therefore can not quantitate effect. Also, useful cut-off levels depend on the specific assay used, and even on the specific lot numbers of reagents. This test might be useful, say, in the case of a child who got into grandpa’s dabigatran and may or may not have ingested a clinically significant amount. Since the peak anticoagulant effect occurs 1 – 3 hours after ingestion, a normal aPTT after 3 hours of observation would be reassuring.

The hemoclot thrombin inhibitors (HTI)  test gave a linear response throughout all dabigatran levels tested, and was judged to be sensitive and reproducible.

The authors conclude:

Due to its widespread use, 24 h a day accessibility, low cost and relatively good sensitivity, aPTT could be used for the monitoring of dabigatran and as a screening test for the risk of bleeding. . . . HTI showed good reproducibility, excellent linear correlation at all doses, simplicity of use, automation capabilities and should therefore be seen today as the gold-standard assay for monitoring of dabigatran after a positive screen test.

Unfortunately, HTI is not readily available at most institutions.

Of course, this all begs the question: if the presumed advantage of dabigatran — reliable pharmacokinetics with need for monitoring — is now being called into question, what’s the justification for using the drug at all?

To read Dr. Mark Mosley’s viewpoint on why emergency physicians should avoid dabigatran, click here.

Related posts:

Dabiagtran and the trauma patient

Dabigatran Toxicity: The Top 10 Questions

Review: the bleeding patient on dabigatran

Dabigatran and the elderly

Dabigatran etexilate: a new challenge for emergency physicians and toxicologists

 

 

 

 

 

2 Comments:

  1. John Di Gregorio Says:

    Question are blood levels established for TDM of this compound?

  2. Leon Says:

    John:

    Not to my knowledge. Monitoring would have to depend on coagulation tests such as aPTT and HTI, as described above.