A 75-year-old man presents to your emergency department via paramedics. His transport time was about 25 minutes. He was driving his car on the highway when he dozed off and hit a light post. There was extensive front-end damage to the car. The airbags didn’t deploy because he was driving a 1963 Buick Riviera. The steering wheel was bent.
He is awake but diaphoretic, and his breathing is rapid but unlabored. He says that his lower chest hurts when he takes a deep breath. He is developing some progressive abdominal tenderness, and a lap belt sign is starting to develop.
He has a history of diabetes (type 2), coronary artery disease, hypertension, and atrial fibrillation. His head and neck exam are normal, except for some facial abrasions. There is no chest wall crepitus, and his lungs are clear. His heart rate is irregular, consistent with atrial fibrillation, which is confirmed on a monitor. His heart rate is 115, and his blood pressure is 115/70.
His medication list includes an angiotensin-converting-enzyme inhibitor and spironolactone for his blood pressure, metformin and a sodium-glucose cotransporter 2 drug for his diabetes, and a direct oral anticoagulant (DOAC).
To make matters worse, his focused assessment with sonography in trauma (FAST) exam reveals free abdominal fluid.
You have a general surgeon on call, and transfer to another hospital is really out of the question. The nearest hospital is 45 minutes away, and it is starting to snow.
You start the IVs and give lactated Ringer’s. Your surgeon is on the way.
What about the DOAC issue?
New Option for Dabigatran
Fortunately, the patient is on dabigatran (Pradaxa). Until recently, trying to reverse DOACs was hard, if not impossible. One option is fresh frozen plasma (FFP), which takes 20 minutes to defrost, has be matched to the patient’s blood type, is hard to give in large volumes quickly, and isn’t at all specific for dealing with DOACs of any type. Recombinant factor VII (NovoSeven) won’t be effective. Factor VII is disproportionately important in the clotting cascade, but factor VII is largely related to warfarin’s mechanism of action and not the DOAC’s. You could also use 4-factor prothrombin complex concentrate, but this is hardly specific with regard to counteracting a direct thrombin inhibitor.
Although you’ve given FFP in the past, you’ve only given 4-factor prothrombin complex concentrate once or twice in the setting of a bleeding patient taking warfarin. You recall that there is a new drug out that specifically counters dabigatran. It is composed of monoclonal antibodies that bind to and inactivate the drug. It is made by the same company that makes dabigatran (Boehringer Ingelheim).
It seems that all of the other options are unlikely to work for this patient. Despite receiving FFP and packed red cells, this patient is still in need of immediate surgery. Your back is to the wall. Normally in situations that are not so dire, you may get away with just waiting. Dabigatran’s plasma concentration peaks in 0.5–2 hours, and depending on when the DOAC was taken, it might be largely gone by the time you see a patient. The anticoagulation half-life is about 12–14 hours in older adults. Given that the drug needs to be given twice a day, maybe you’d get lucky and the accident will have occurred just before the patient’s second dose of the day.
However, seeing that our patient is definitely bleeding and on the hypotensive side, do you pull the trigger? Do you ask the pharmacy for the antidote, idarucizumab (Praxbind)? You’re about to give a drug that will quickly reverse this patient’s DOAC (90 percent of the dabigatran will be reversed in about four hours).
Is there any other option? What about tranexamic acid? This drug stops clots from lysing. Would there be any reason not to use it? It’s cheap, safe, and readily available, but it’s not the specific reversal agent for dabigatran. It would seem that, in this case, it may be a reasonable option.
What about the cost of these drugs? Although it is always difficult to nail down the actual cost of drugs to a hospital (due to variables such as system discounts, middle man markups, and difficulty verifying prices found on the internet), prices are hefty, except for tranexamic acid.
In a 2016 article in Critical Pathways in Cardiology, the wholesale acquisition price of the usual 5 mg dose of Praxbind was listed at $3,452.50 ($3,662 on Drugs.com).1 Depending on the dose needed, NovoSeven’s price can vary from $2,262 to $18,035 (Drugs.com), and GoodRx says price ranges from $2,152 to $17,620 with its discount coupon at Costco. According to Family Practice Notebook (FPNotebook.com), 4-component prothrombin complex concentrate costs $4,500, while FFP costs $250.
Rarely discussed is the responsibility of hospitals to stock drugs that are uncommonly used, very expensive, and potentially lifesaving. The shelf life of Praxbind is 24 months. Is it reasonable to anticipate that all hospitals will have a supply on hand? With about 1,200 critical-access hospitals in the country, each having 25 acute care beds or fewer, many where weather and terrain may make transfers to larger centers impractical at times, what is the legal risk of not stocking certain essential drugs?
Case Resolution and the Evolution of Anticoagulation Reversal
Your patient receives idarucizumab early during his emergency department stay, and despite a somewhat rocky course, he survives his surgery for a ruptured liver, thanks to the specific reversal agent for dabigatran and due to the good fortune that he was taking the one DOAC with a reversal agent.
In more recent developments, the first Xa DOAC reversal agent, andexanet alfa (Andexxa), was approved by the FDA in May 2018. It reverses both rivaroxaban (Xarelto) and apixaban (Eliquis), but the indications do not cover edoxaban (Savaysa) and betrixaban (Bevyxxa).
Depending on the dose of rivaroxaban or apixaban being taken, either a low-dose or high-dose regimen of andexanet alfa is advised. The Medical Letter indicated that the drug had very limited availability (10 hospitals had it at the time of publication), but supplies are expected to increase in early 2019.2 The cost is $49,500 for the high dose and half that for the low dose.
Dr. Bukata is medical director for the The Center for Medical Education and adjunct clinical professor of emergency medicine at LAC+USC Medical Center in Los Angeles.
- Buchheit J, Reddy P, Connors JM. Idarucizumab (Praxbind) formulary review. Crit Pathw Cardiol. 2016;15(3):77-81.
- Andexxa—an antidote for apixaban and rivaroxaban. Med Lett Drugs Ther. 2018;60(1549):99-101.