Thursday, March 7, 2013

(F)Utility of Hemodialysis for Dabigatran Reversal

The case: A 65-year-old male presents to the emergency department today after a witnessed fall on his head by his wife. He was diagnosed with non-valvular atrial fibrillation two months ago and was placed on dabigatran 150 mg PO BID. He has fallen several times in the past week. His last dose of dabigatran was 6 hours ago. CT scan of the head shows a small right subdural hematoma with a 6-mm leftward midline shift. His Hgb is 8.2 mg/dL and his SCr is 3.6 mg/dL.

This case in and of itself is quite challenging, and there has been much discussion regarding the use of treatment strategies to reverse the anticoagulation effects of dabigatran. This may include the use of hemostatic agents such as 3- and 4-factor prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (aPCC), and/or recombinant factor VIIa (rFVIIa). Other detoxification strategies that have been investigated include the use of hemodialysis in this setting, which is what I want to focus on. 

Taking a closer look at the pharmacokinetic properties of dabigatran, it is of relatively small molecular weight (471 Da) and it is not highly bound to plasma proteins (35%), which theoretically makes it an ideal compound for removal through hemodialysis. In fact, many studies will commonly cite this trial as a basis for demonstrating that hemodialysis is effective for the removal of dabigatran, which touts that 62 to 68% of the drug is extracted after two and four hours of hemodialysis, respectively. However, let us take an even closer look at the patient population and methodology of this study. Six patients with stage 5 chronic kidney disease received a single dose of 50 mg of dabigatran before undergoing a four-hour session of hemodialysis. First of all, this is less than the FDA-approved dosing strategy of dabigatran (75 to 150 mg by mouth twice daily). [Not to mention that a 50-mg capsule is not formulated by the manufacturer.] In addition, because a single dose was administered, steady state levels of dabigatran were not achieved, and so the percentage of dabigatran removed through this process cannot be applied to patients that we commonly encounter in clinical practice. 

The question now becomes whether the results of this study can be extrapolated to cases such as the one described of our patient above. In one case report, hemodialysis was performed in a patient who was chronically taking dabigatran prior to needing to undergo emergent cardiac surgery. After a 2.5-hour session of hemodialysis, the thrombin time decreased from nearly 90 seconds to approximately 60 seconds. Although the thrombin time was still prolonged (and sustained for nearly 24 hours after surgery), the patient did not experience any bleeding complications during and after the surgery. In another recently published case report, emergent hemodialysis was used in an attempt to clear dabigatran from a patient with an intracranial hemorrhage. The patient described in the case did improve clinically, as administration of other treatment modalities to control the intracranial hemorrhage took place. The investigators of this study had chromogenic assays available to measure serum concentrations of dabigatran, and they observed a rebound phenomenon take place after a 3-hour session of hemodialysis, which demonstrates that because of its large Vd (50 to 70 L), the drug distributed from the tissues to the bloodstream. The authors concluded that continuous renal replacement therapy may be necessary to use as an adjunct to emergent hemodialysis to minimize the possible complications of this rebound phenonomenon. 

Another thing to consider when determining whether or not to dialyze a patient as described in the case above is the matter of logistics. Sure, it may seem like a great idea to initiate hemodialysis. However, a nephrology consult would have to be obtained. Once the nephrology team is on board, then the process of actually getting the patient to a hemodialysis bed is the next step. This may take some effort and resources, and there could potentially be a time delay of a few hours from the time that the patient initially presented to the emergency department. 

We do not have a clear cut answer of the treatment approach for reversing the anticoagulant effects of dabigatran in the setting of life-threatening hemorrhage. Hemodialysis may be used as an option in adjunct to other hemostatic strategies. However, as highlighted here and as demonstrated with other medications, one needs to bear in mind that studies that the manufacturer of the drug puts out may be vastly different from those that are relevant and applicable to clinical practice.

2 comments:

  1. Great post! As you mention, there are some significant limitations to the hemodialysis article, which outlines the importance of questioning even some of our more trusted drug resources (eg, Micromecedex, Lexi-Comp, etc.), digging into the references, and pulling up the primary literature for yourself!

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    1. Thank you for your feedback! I have seen this happen too often, where the information that exists in drug references is taken for granted without questioning the actual data behind it. It somewhat resembles the rule of thumb that I go by with journal articles as well: never read the abstract first. Developing and refining our ability to thoroughly evaluate published literature is key.

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