Dream drugs or nightmares in the making?

You’ve taken care of this sort of patient countless times: A 65-year-old is brought to the emergency department after suffering a slip and fall and gets a small goose egg on the her forehead. She wasn’t knocked out, it wasn’t syncope, and the rest of her exam is completely normal except for an irregularly irregular rhythm. She says her doctor just put her on a new medicine “so I don’t get a stroke”. Your eyes dart to her meds list: Xarelto. Xarelto? What the heck is that?

It is time for a review of a subject nightmares are made of: the clotting cascade. You know it is a physiologic miracle, carefully breaking down incidental clots you make every day during your sedentary, channel-surfing hours while making sure you don’t bleed to death when you cut yourself shaving. Despite the fact you once learned the clotting cascade, after passing your boards you defaulted to a “then a miracle occurs” understanding of how it all works.

On a day-to-day basis, every practitioner knows that clots happen and can be devastating. Conditions such as deep venous thrombosis and atrial fibrillation tee patients up for potential catastrophe. In our pharmacologic bag of tricks are medications, some tried and true, others shiny and new, available to mitigate this risk, and they are routinely available, albeit in a wide cost range.

The dark side of these medications is well known. Because they stop clotting, these drugs increase the risk of bleeding. Warfarin, the commonly prescribed vitamin K antagonist, can be nightmarish to dose and may be affected by something as seemingly benign as a spinach salad or a dose of sulfa. This variability necessitates routine monitoring, yet another downside that we’d rather do without.

The ideal anticoagulant would be one that is easy to dose, causes predictable anticoagulation that does not need monitoring, is not be affected by diet or other medications, is inexpensive and readily available, and is easily and rapidly reversible should bleeding occur. Recently released medications provide several of these characteristics, but at what may be a high price if someone taking them is unfortunate enough slip and fall: They can turn a minor head bleed into a lethal one, and there is virtually nothing anyone can do about it.

Antiplatelet Agents: Clopidigrel and Prasugrel
Before discussing the new anticoagulants, it is reasonable to pause for a brief homage to the newer antiplatelet agents. Clopidogrel (Plavis®) and prasugrel (Effient®) are the behemoths of the antiplatelet world. Thienopyridine derivatives, they block the ADP receptor on the platelet necessary to activate it. When compared to aspirin, both agents significantly increase the risk of bleeding. In general, prasugrel is more effective than clopidogrel, but causes more major bleeding events. Although these agents can cause bleeding, the good news is that they are reversible with platelet concentrates and DDAVP. The bad news: Reversal takes 15-30 minutes.

Vitamin K Antagonists: Warfarin
Warfarin has been around for what seems like forever, and most physicians are aware of the benefits and dangers of this agent. A vitamin K antagonist, warfarin blocks the production of vitamin K dependent coagulation factors (II, VII, IX and X), and induces a factor deficiency state. Anything that interferes with vitamin K absorption or activity may alter the coagulation status of someone on warfarin. Patients on chronic warfarin therapy have an annual risk of major bleeding of 0.5-1 percent, and an annual risk of intracranial hemorrhage of 0.2-0.3% per year. The risk of bleeding is directly related to the height of the INR. For instance, an INR over 3.0 doubles the risk of bleeding compared to INRs between 2.0 and 3.0. The elderly are at particular risk of bleeding.

If a patient stops taking warfarin, it takes 60-80 hours to achieve hemostasis. This process can be accelerated by administering vitamin K, but even in the best of circumstances it only shortens the time to hemostasis to 12 hours, which is virtually useless if a patient is actively bleeding. While FFP contains all the deficient factors, the large amount necessary to reverse the coagulopathy may be prohibitive.

Fortunately, prothrombin complex concentrates contain some or all of the coagulation factors deficient in patients on warfarin. Profilnine and Bebulin contain 3 factors; Beriplex, Octaplex and the recently approved Kcentra contain factors II, VII, IS and X, as well as protein C and S. Reversal of anticoagulation is almost immediate. While these agents are effective, some things still remain unclear about their use. In patients with life threatening bleeding, 4-factor PCCs are the way to go and their use is supported in the guideline by the American College of Chest Physicians. In patients with less than potentially lethal bleeding, however (particularly if they are on the warfarin because they have a mechanical valve), the clotting associated with use of PCCs may be life threatening in itself, and care must be taken to balance the risks and benefits of using them.

Direct Thrombin Inhibitor: Dabigatran (Pradaxa®)
Hirudin, the prototype direct thrombin inhibitor, was derived from leech saliva (seriously). Argatroban and Dabigatran are newer direct thrombin inhibitors. Dabigatran has been approved for DVT prophylaxis after surgery and stroke prevention in patients with atrial fibrillation. The half-life is 12-17 hours in patients with normal renal function. As it is cleared by both the liver and kidneys, this agent is not recommended in patients with renal failure or impaired hepatic function. Compared to warfarin, dabigatran is touted for its immediate anticoagulation, lack of transient hypercoagulable state, minimal interactions with food and other drugs and lack of any required testing to monitor its efficacy. It does interact with a few drugs, such as rifampin, quinidine, ketoconazole, verapamil, amiodarone, and clarithromycin.

For stroke prevention, trials show dabigatran is as effective as warfarin and has the same or less bleeding risk (which runs around 3%). Older patients seem to be at a higher risk of bleeding.

So, what to do if a patient is bleeding? Discontinue the drug; it will be pretty much gone in 12-13 hours. Be sure to also stop any other drugs that might potentiate bleeding (aspirin, etc). And obviously provide supportive care. In theory, prothrombin complex concentrates may work, providing thrombin that is competitively blocked by dabigatran. This effect, however, is based on studies of a scant number of healthy volunteers showing they reverse dabigatran-induced anticoagulation, and it is not clear they will have the same effect on a bleeding patient with comorbidities. Finally, call your nephrologist. That’s right, a nephrologist. One third of the drug is protein bound, so the remaining two thirds can potentially be removed with dialysis. Other agents (FFP, rVIIa, tranexaminic acid, cryoprecitipate, protamine, DDAVP and aminocaproic acid) are likely unhelpful.

In an interesting twist, a recent meta-analysis of 7 RCTs comparing dabigatran to warfarin. Enoxaparin or placebo showed a significantly higher risk of AMI or ACS (1.19 vs. 0.79). Stay tuned.


Factor Xa Inhibitors: The “Xabans” (rivaroxaban - Xaralto®, and apixaban - Eliquis®)
The “xabans” are newly available oral agents; both rivaroxaban and apixaban have been approved by the FDA since 2010. Because their onset of action is rapid (peaks in 2-4 hours), parenteral bridging is often unnecessary. While anticoagulant effect is predictable and monitoring of anticoagulation is not required, a special assay is available if it becomes necessary to monitor the activity of the agent. Unfortunately for EPs, this test may not be available in a fashion timely enough to help in treating a patient in the emergency department.

Rivaroxaban is approved for surgical DVT prophylaxis, stroke prevention in nonvalvular atrial fibrillation and treatment of DVT and PE. To date, apixaban is only approved for stroke prevention in valvular atrial fibrillation. The half-life of these agents is around 5-14 hours (more on this aspect later). For DVT prophylaxis, studies show the xabans have a lower bleeding risk and similar efficacy as low molecular weight heparin for DVT prophylaxis, and in patients with atrial fibrillation they are noninferior to warfarin in preventing stroke with a lower risk of bleeding.

While these drugs have less drug interactions than warfarin, the azoles, carbamazepine, rafamycins and St. Johns wort may interact with the xabans. Also, as the drugs are primarily renally cleared, their use is not recommended in patients with renal dysfunction (CrCl < 30 ml/min). Additionally, they should be avoided in patients with significant hepatic impairment.

So what can you do to reverse someone on a xaban who has significant bleeding? Well, as the drugs have a relatively short half-life, you can wait until the anticoagulant effect wears off (in young, healthy patients, for rivaroxaban, it’s 5-9 hours. For apixaban, it’s 8-15 hours). That’s nice in theory, but it’s too long if there is serious bleeding. If they just took the medication, a Hail Mary option is to administer activated charcoal, but if the drug is absorbed it might just create a bleeding patient who looks like a bloody piece of licorice. Are there any better options? To date, no antidotes or reversal agents have been found. As the drugs are highly protein bound, they are not dialyzable. PCCs are recommended, based more on “What the heck else can you do?” than on any reasonable data.

But wait, there’s more! The FDA recently released a warning regarding the xabans: “Discontinuing (Xarelto, Eliquis) in patients with nonvalvular atrial fibrillation increases the risk of stroke”. That means even ONE DOSE. The implication for EPs who board patients for over 12 hours is clear; you may be held accountable if a dose of this “chronic medication” is missed and the patient strokes out.

Other Issues and What The Future May Bring
The new anticoagulants pose another challenge for emergency physicians. What do you do if a patient needs a lumbar puncture? You can’t follow coagulation studies to see if the patient is anticoagulated, and, even if it were possible, reversing these agents for an LP may be relatively contraindicated. If the patient is on a xaban, it is recommended to stop the drug, wait for a period of time (it is not clear exactly how long, but “until the next day” is often noted) to perform the procedure. If an LP is performed, the xabans should not be restarted until > 24 hours after any traumatic puncture. (But what about that FDA warning regarding the risk of stroke if the xabans are stopped in patients with atrial fibrillation?)

What does the future hold? To date, most of the data regarding safety and efficacy of these agents comes from controlled studies. Unleashed on the medical community and its patients, it is unclear if these agents will prove to be the solution to the anticoagulation quagmire or cause a plethora of cases of irreversible bleeding. Time will tell, but for the now treating patients on these agents who come to the emergency department poses new challenges.

Dr. Birnbaumer is a senior faculty member in the Department of Emergency Medicine at Harbor-UCLA Medical Center, Torrance, California and Professor of Clinical Medicine at the University of California-Los Angeles.


# DrAaron Reilly 2013-07-12 06:07
AClearanceOf Small Points: Dabigatran Clearance Is More Renal Dependent than Rivaroxaban, Since Riva Is Primarily Metabolized By The Liver, And Dabi Is Cleared Renally, But intact. Also, The Table Has Some Omissions (I.e. FFP For Vit K Antag), And FEIBA Is Not Mentioned. Thank ForThe Good Overview

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