The FDA-approved drug dabigatran is being marketed as a safe alternative to Coumadin. But without a proven reversal agent available, it has the potential to create a new set of complications, and send unsuspecting patients right back to the ED.
A 77-year-old patient presented to the ED a few months ago after gently falling over onto a carpeted floor while using his walker. The patient appeared well with the exception of dry mucous membranes. He complained of his typical back pain (upper, mid-thoracic) and he reported decreased P.O. intake. His initial blood pressure was 76/48. With no other physical findings, serial fluid boluses were ordered to address the potential of dehydration as the cause of his hypotension and subsequent fall. A further diagnostic evaluation was taken while the fluids were being administered. Sure enough, his urinalysis showed positive nitrate with greater than 100 WBCs. In addition, his BUN and creatinine were 56 and 3.1, respectively. These changes were new. His WBC count was 10.2, Hgb was 11.0, and he was afebrile. Before you ask, his ECG showed an AV-sequential pacemaker without any changes from previous.
So, we had a clinically dehydrated 77-year-old patient with new onset renal failure, most likely secondary to his dehydration associated with his UTI and poor P.O. intake. With a negative review of systems and relatively negative exam, his hypotension fit the picture. However, after two 500cc fluid boluses, his blood pressure hadn’t changed. In a non-septic patient with dehydration, an improvement was expected. However, when the square peg didn’t fit the round hole, it was time to broaden the differential diagnosis. Again, he was asked about his history: “Any new medications? Are you sure this is the same pain you always have? Are you on any blood thinners?” He replied, “Nope. Exactly the same, I used to be on Coumadin but my doctor took me off of that a month ago.” Although this patient’s pain was typical for him, a CT of the chest was ordered.
The CT revealed a pericardial effusion that was further confirmed as cardiac tamponade by bedside 2-D echo, following a call from Radiology reporting a pericardial effusion. The Echo confirmed early tamponade. Now there seemed to be an explanation.
Superimposing tamponade on dehydration likely limited the physical findings of tamponade to refractory hypotension. But what was the cause of the tamponade? On further more insistence history, it turned out the patient was on Pradaxa and Plavix. But now we had a relatively bare cabinet of antidotes. As a result, he received FFP and vitamin K and an emergent pericardial window evacuation of 1000 cc of blood from his acute hemopericardium.
With its narrow therapeutic window, ugly side-effect profile and need for drug monitoring, Coumadin leaves much to be desired, and many physicians have looked forward to a “white knight” drug to take its place. But be careful what you wish for. If you are too needy and too desperate, as we all have been to avoid the use of Coumadin, we may be enticed into early adoption of an alternative that may actually be worse. (I may have been an early adopter of parachute pants in the 80s, but I learned my lesson.) The combination of Coumadin’s drawbacks and the ramped up marketing efforts for Pradaxa has resulted in skyrocketing use of the new drug.
As bad as Coumadin can be, it is inexpensive – less than $0.50 a pill – and its shortcomings are very well known. On the other hand, a daily course of Pradaxa (150 mg BID) will cost over $8. But I certainly wouldn’t advocate the continued use of Coumadin from a cost perspective. If we have something safer, the higher cost is money well spent. The point, however, is that dabigatran’s safety is truly debatable, despite the fact that it was approved by the FDA. (There have been a laundry list of bad actors pulled from the market for safety reasons, despite the FDA’s willingness to approve them.)
At an EM conference in February attended by many international physicians, I asked the participants, “Has anyone seen any complications from Pradaxa yet?” I expected just a few, but I was amazed to see almost half of the audience raise their hands. Despite the fact that no case reports have yet been published, it appears, anecdotally, that real safety issues do exist.
Dabigatran has one indication, the prevention of ischemia in non-valvular atrial fibrillation, and I’ll concede that the evidence seems clear that it is as effective, but not superior, to Coumadin for this purpose (N Engl J Med, 17;361(12):1139-51, September 2009). However, the lure of this drug is to broaden its application to other cases due to the fact that it doesn’t require monitoring, can reduce unnecessary inpatient stays for bridging with heparin and somehow, is safer than Coumadin. The first two statements are true.
However, the latter likely is not, especially as it pertains to older patients. One study, revisiting the RE-LY trial cited above, looked at the age cut off of 75 years. They reported that, compared to Coumadin, 5.10% versus 4.37% experienced major bleeding, and those under 75 years experienced a rate of 2.12% on dabigatran (Circulation, 31;123(21):2363-72, May 2011). So, particularly above the age of 75, Pradaxa may pose a greater risk to major bleeding, even more than Coumadin. And real problem is that there is no antidote or proven reversal agent for this direct thrombin inhibitor.
Dabigatran has very predictable dose response, and thus, frequent monitoring is not necessary. As a matter of fact, peak levels are reached two hours post administration and by as early as 4 to 6 hours, levels drop by 70% or more due to its large volume of distribution. Furthermore, 80% is cleared through the renal system within 12 hours.
Dabigatran doesn’t affect cytochrome p450. Thus, there are very few, if any, medication or dietary interactions. Another fun fact is that there is no need for bridging anticoagulant therapy, while waiting for dabigatran to take effect. Here’s why. We know that Coumadin works by inducing a state of vitamin K deficiency, particularly impacting factors VII, IX and X. What many are not aware of is that protein C and protein S are also vitamin K dependent. Thus, Coumadin creates a temporary hypercoagulable state from this inhibitory effect of protein C and S. Hence, there is a need for a bridging anticoagulant when initiating Coumadin that is not necessary for dabigatran.
Due to a lack of protein binding, dabigatran is easily dialyzable. It is also absorbed by charcoal, making gastric decontamination a viable option for recent ingestions. In addition, due to the drug’s rapid clearance, immediate discontinuation of the drug, theoretically, goes a long way toward limiting the anticoagulant effect of this drug.
Although frequent monitoring isn’t necessary, that’s a good thing, as we have no reliable test to quantitatively measure the patient’s degree of anticoagulation. The best we can do is to identify whether or not the patient is experiencing any anticoagulation effect. The answer is limited to a qualitative “yes” or “no.” Although unfortunately it is not available in many labs, thrombin time has a linear dose response relationship with dabigatran and will likely be the most effective test for assessing the anticoagulant activity of this drug. The aPTT is, perhaps, the best option currently. The aPTT will rise very quickly after an oral dose. So, particularly in a suspected overdose, you can tell quickly if the patient has ingested any dabigatran. However, the aPTT will peak at about 2-3 times of the control value, regardless how much dabigatran they’ve taken or what extent of anticoagulant effect they are experiencing from it; this test does not have a linear dose response with dabigatran. The INR will also increase and plateau at around 2.0. However, this takes much longer to increase, making this test less useful. Our index patient’s INR was 3.0, and his aPTT was 2.5 times normal. Following a rocky inpatient course, the patient was discharged and is currently on no anticoagulants.
Without a doubt, the biggest drawback of dabigatran is the lack of a proven reversal agent. The goal should be to either increase prothrombin/thrombin and/or to induce a hypercoagulable state. FFP can certainly be used, as it does contain some prothrombin. However, the low levels present are probably suboptimal for reversal. Current thinking, although not proved, is that prothrombin complex concentrates and recombinant factor VII are the most effective agents we currently have available. Vitamin K is completely ineffective for the treatment of dabigatran-induced coagulopathies, as dabigatran has no effect on vitamin K.
With a drug that has significant risk for major bleeding complications, it would seem logical to delay FDA approval until a proven antidote is identified and tested. Other countries have, in fact, taken this approach. One Australian hematologist who attended the conference previously mentioned advised me that the drug had been released in Australia, but due to the high incidence of bleeding complications, the release had been suspended, pending further investigation.
Although EPs probably won’t be writing for Pradaxa too often, just like with Coumadin, we’ll be left holding the bag, cleaning up its complications. The first step is to add this drug to the “active ask list.” “Are you on Coumadin, Plavix or Aspirin?” Now, we need to add dabigatran to that list. We need to recognize the limitations to currently available laboratory testing with respect to dabigatran and develop a strategy for reversal, including potential antidotes and possibly dialysis (and don’t forget supportive care, such as blood transfusions). Dabigatran is effective and clearly has some desirable attributes. However, in general, this drug is being marketed as a safe alternative to Coumadin, a claim that is probably overstated and seems to result in a false sense of confidence.
Dr. Kevin Klauer is the editor-in-chief of Emergency Physicians Monthly, the CMO of Emergency Medicine Physicians, and the vice speaker of the ACEP Council.