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Rick Bukata, MD
President of The Center for Medical Education

New Anticoagulants — New Issues

by Michael Menchine, MD

Michael Menchine, MD

Several novel oral anticoagulant agents (NOACs — also known as target-specific anticoagulants) debuted within the last several years and offer the first new option for anticoagulation in decades. Offering the benefits of easy dosing regimens, minimal food or drug interactions and eliminating the need for monitoring of blood anticoagulation status, these drugs seem to offer significant benefits over warfarin.

For emergency physicians, however, these agents pose significant issues. To date, there are no antidotes available to reverse their anticoagulant effect. Clearly, this poses a potentially life-threatening problem in patients with significant bleeding. Also, none of the currently available coagulation testing can reliably determine the patient’s anticoagulation status (with the exception of the aPTT, which will be covered later). As a result, procedures such as lumbar punctures may be contraindicated until it can be assured that the drug effect has worn off. At this point there are no reported cases of overdose with these agents, and the approach to treating them will prove challenging as standard coagulation studies cannot be used to determine the degree of anticoagulation (if any) these patients may have. Finally, being on a NOAC is considered a contraindication to giving thrombolytics in stroke, eliminating this potential treatment option in these patients.

The mechanism of action of these agents is distinctly different from that of warfarin. Warfarin causes a factor deficiency state by depleting vitamin K-dependent coagulation factors (II, VII, IX, X and proteins S and C). As a result, reversal of anticoagulation with a vitamin K antagonist (VKA) is feasible by both allowing regeneration of these factors (by giving vitamin K) and by replacing them (i.e. giving FFP or prothrombin complex concentrates). The NOACs, however, work stoichiometrically at the factor level, and the parenteral administration of additional factor may not reverse their effect as the drugs will affect the exogenous factors in the same way as they do the patient’s endogenous factors.

These agents are currently approved for DVT prophylaxis in orthopedic surgery, treatment of DVT and PE, and/or for the prevention of stroke in patients with nonvalvular atrial fibrillation (about 5% of the population over 65). These agents are NOT approved for anticoagulation of patients with mechanical valves. Most of the studies of the efficacy of these agents have been randomized, controlled, noninferiority studies; that is, the agents are not worse than (but may not be better than) warfarin. There is only one study (apixaban) that shows the NOAC is better than warfarin.

While the release of these agents has been met with enthusiasm, their widespread use may reveal more bleeding complications than noted in the randomized, controlled trials that have been published to date. Little research has been done to address how to treat significant bleeding in patients on these agents. As a result, most of what is recommended is based on animal and normal volunteer studies, and very few of these have been published. At this point most of the recommendations regarding treatment of hemorrhage in patients on these agents are based on consensus panels and, clearly, much more research needs to be done to address this issue.

This chapter will focus on what is known about these agents to date.

QUESTION: WHAT IS DABIGATRAN AND WHAT ARE ITS INDICATIONS?
Dabigatran (Pradaxa) is the only oral direct thrombin (Factor IIa) inhibitor presently available in the US. It was approved by the FDA in October of 2010. It has recently gained FDA approval for long-term anticoagulation in nonvalvular atrial fibrillation (instead of warfarin). The most comparable drugs to dabigatran are the intravenous direct thrombin inhibitors (bivalirudin, hirudin, argatroban). Recently dabigatran received a class I recommendation from the American College of Cardiology and the American Heart Association for the treatment of nonvalvular atrial fibrillation. In Europe, dabigatran has been approved for the prevention of DVT in orthopedic patients. Dabigatran is being investigated for use in acute venous thromboembolism and acute coronary syndrome but is NOT approved in any country for these indications. Given the narrow therapeutic window, need for monitoring of INR with warfarin therapy and intense marketing campaign promoting dabigatran, a rapid rise in the number of patients taking this novel oral anticoagulant can be expected in the coming years. Of note, this agent has NOT been approved for anticoagulation of patients with mechanical valves, and warfarin remains the treatment of choice for this indication.

  1. 2011 ACCF/AHA/HRS FOCUSED UPDATE ON THE MANAGEMENT OF PATIENTS WITH ATRIAL FIBRILLATION (UPDATE ON DABIGATRAN) Wann, L.S., et al, J Am Coll Card 57(11):1330, March 15, 2011
    METHODS: This report, from the American College of Cardiology Foundation / American Heart Association Task Force on Practice Guidelines, presents an update to a 2006 guideline focused on the use of dabigatran (Pradaxa, Boehringer Ingelheim, $4.10 per 150mg capsule on drugstore.com) in patients with nonvalvular atrial fibrillation (AF). RESULTS: The antithrombotic, dabigatran, was approved by the FDA in October 2010 for patients with AF. It is given as a fixed dose without laboratory monitoring. It has a half-life of 12–17 hours, and there is no specific antidote. Supportive treatment for severe related bleeding includes fresh frozen plasma or packed red blood cells. In the RE-LY trial, published in 2009, dabigatran (110mg and 150mg twice daily) was compared with warfarin (to a target INR of 2.0–3.0) in 18,113 patients with nonvalvular AF and at least one risk factor for stroke. The stroke rate per year was 1.71% in patients on warfarin vs. 1.54% and 1.11% in the 110mg and 150mg dabigatran dosing groups, respectively. Corresponding rates of major bleeding per year were 3.57% vs. 2.87% and 3.32%, respectively. Patients taking dabigatran had a higher rate of myocardial infarction (0.81% and 0.82% in the 150mg and 110mg dosing group vs. 0.64% in patients treated with warfarin). There was no difference between the groups in mortality. CONCLUSIONS: The Task Force makes the following recommendation: “Dabigatran is useful as an alternative to warfarin for the prevention of stroke and systemic thromboembolism in patients with paroxysmal to permanent AF and risk factors for stroke or systemic embolization who do not have a prosthetic heart valve or hemodynamically significant valve disease, severe renal failure or advanced liver disease” (Level of Evidence: B). 7 references (reprints@elsevier.com for reprints) 9/11 — #14

QUESTION: DOES DABIGATRAN WORK FOR NONVALVULAR ATRIAL FIBRILLATION?
The RE-LY trial was declared to be a noninferiority trial — guess it wasn’t trying to show that dabigatran was better than warfarin in atrial fibrillation — kind of a strange concept. In this 18,133-patient randomized comparison of two different doses of dabigatran vs. standardized warfarin doses, dabigatran given at a dose of 110mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. When compared with warfarin, dabigatran administered at a dose of 150 mg was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. Importantly, the cost for dabigatran is approximately $5.45 per 150mg capsule (Costco) or $10.90 per day (dabigatran is dosed BID) while the cost for 5mg of warfarin is $0.47. INR testing costs about $20 a month for patients on warfarin.

  1. DABIGATRAN VERSUS WARFARIN IN PATIENTS WITH ATRIAL FIBRILLATION, Connolly S.J., et al, N Engl J Med, 17;361(12):1139–51, September 2009 
    BACKGROUND: Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use. Dabigatran is a new oral direct thrombin inhibitor. METHODS: In this noninferiority trial, we randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive, in a blinded fashion, fixed doses of dabigatran — 110 mg or 150 mg twice daily — or, in an unblinded fashion, adjusted-dose warfarin. The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism. RESULTS: Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority) and 1.11% per year in the group that received 150 mg of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority). The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group receiving 110 mg of dabigatran (P=0.003) and 3.11% per year in the group receiving 150 mg of dabigatran (P=0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% per year with 110 mg of dabigatran (P<0.001) and 0.10% per year with 150 mg of dabigatran (P<0.001). The mortality rate was 4.13% per year in the warfarin group, as compared with 3.75% per year with 110 mg of dabigatran (P=0.13) and 3.64% per year with 150 mg of dabigatran (P=0.051). CONCLUSIONS: In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage.

QUESTION: HOW DOES DABIGATRAN DIFFER FROM WARFARIN AS AN ANTICOAGULANT?
Dabigatran is a competitive direct thrombin (factor IIa) inhibitor. It acts very far down the clotting cascade (in the final common pathways) to inhibit thrombin’s ability to initiate platelet aggregation and cleave fibrinogen to fibrin.

Unlike warfarin, dabigatran displays a stable and predictable hematologic response following oral administration making frequent lab testing unnecessary (in fact, it will be demonstrated that standard anticoagulation tests are not reliable either). This is clearly an advantage over traditional warfarin therapy. Dabigatran works directly as a thrombin inhibitor. Ingestion of dabigatran causes immediate anticoagulation (unlike warfarin which, of course, requires several days of therapy before anticoagulation is achieved through inhibition of liver synthesis of II, VII, IX and X). Also, because anticoagulants protein C and protein S are vitamin K-dependent, administration of warfarin may temporarily induce a hypercoagulable state. Dabigatran, as a direct thrombin inhibitor, does not demonstrate this procoagulant tendency, thereby negating the need for “bridging” therapy with heparins.

QUESTION: HOW IS DABIGATRAN ABSORBED AND METABOLIZED?
Peak plasma concentrations occur within 2 hours of administration. The drug has a large volume of distribution causing levels to drop by >70% in 4–6 hours. Approximately 80% of plasma dabigatran is excreted in the urine with an elimination half-life of approximately 12 hours; the remaining 20% is excreted in bile. Because of the predominant renal elimination, doses must be adjusted for patients with renal impairment (75mg BID rather than 150 BID) as the elimination half-life increases to approximately 24 hours when creatinine clearance is between 15–30ml/min. Dabigatran is not recommended to be used in patients undergoing hemodialysis. Dose adjustment is not recommended for patients with impaired hepatic function.

Dabigatran does not induce cytochrome p450 activity and is reported to have very few drug interactions (unlike warfarin). Theoretically, coadministration with rifampin may result in decreased dabigatran levels and efficacy but the clinical significance of this interaction is not known. As some patients with nonvalvular atrial fibrillation and lower ejection fraction may also use digoxin, it is worth noting that dabigatran does not appear to affect digoxin metabolism.

QUESTION: WHAT IS THE BLEEDING RISK OF DABIGATRAN AND HOW DOES IT COMPARE WITH WARFARIN?
In the RCTs, using the manufacturer recommended dose of 150mg BID, the rate of major bleeding was 3.11% per year (compared with 3.36% for warfarin). The rate of intracranial hemorrhage was 0.1% per year (compared with 0.38% for warfarin). A subgroup analysis of the 18,000 patients in the RE-LY trial showed that older patients (particularly over age 75) had a substantially higher risk of bleeding — 5.1% per year — compared to the younger group. It should be emphasized that these bleeding episodes occurred in well-monitored clinical trials. The rate of bleeding will likely be higher in non-experimental settings. In fact, in January 2014 the FDA announced that it will be conducting a study to address this concern using the Mini-Sentinel Distributed Database, gathering real-use data to determine the rates of bleeding in new-users of the two agents in the “real world” setting (and it is likely the FDA will do the same with the xabans).

  1. RISK OF BLEEDING WITH 2 DOSES OF DABIGATRAN COMPARED WITH WARFARIN IN OLDER AND YOUNGER PATIENTS WITH ATRIAL FIBRILLATION: AN ANALYSIS OF THE RANDOMIZED EVALUATION OF LONG-TERM ANTICOAGULANT THERAPY (RE-LY) TRIAL, Eikelboom J.W., et al, Circulation, 31;123(21):2363–72, May 2011 
    BACKGROUND: Dabigatran 150 and 110 mg twice a day and warfarin are effective for stroke prevention in atrial fibrillation. The purpose of this study was to compare their risks of bleeding in the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial. METHODS AND RESULTS: The RE-LY trial randomized 18 113 patients to receive dabigatran 110 or 150 mg twice a day or warfarin dose adjusted to an international normalized ratio of 2.0 to 3.0 for a median follow-up of 2.0 years. Compared with warfarin, dabigatran 110 mg twice a day was associated with a lower risk of major bleeding (2.87% versus 3.57%; P=0.002), whereas dabigatran 150 mg twice a day was associated with a similar risk of major bleeding (3.31% versus 3.57%; P=0.32). There was a significant treatment-by-age interaction, such that dabigatran 110 mg twice a day compared with warfarin was associated with a lower risk of major bleeding in patients aged <75 years (1.89% versus 3.04%; P<0.001) and a similar risk in those aged >=75 years (4.43% versus 4.37%; P=0.89; P for interaction <0.001), whereas dabigatran 150 mg twice a day compared with warfarin was associated with a lower risk of major bleeding in those aged <75 years (2.12% versus 3.04%; P<0.001) and a trend toward higher risk of major bleeding in those aged >=75 years (5.10% versus 4.37%; P=0.07; P for interaction <0.001). The interaction with age was evident for extracranial bleeding, but not for intracranial bleeding, with the risk of the latter being consistently reduced with dabigatran compared with warfarin irrespective of age. CONCLUSIONS: In patients with atrial fibrillation at risk for stroke, both doses of dabigatran compared with warfarin have lower risks of both intracranial and extracranial bleeding in patients aged <75 years. In those aged >=75 years, intracranial bleeding risk is lower but extracranial bleeding risk is similar or higher with both doses of dabigatran compared with warfarin. In studies of health volunteers receiving escalating doses of dabigatran 6/8 subjects receiving 400mg TID and 2/8 receiving 200mg TID developed bleeding symptoms within 7 days (mostly hematomas at blood draw sites but gum bleeding was also reported.
  2. THE PHARMACOKINETICS, PHARMACODYNAMICS AND TOLERABILITY OF DABIGATRAN ETEXILATE, A NEW ORAL DIRECT THROMBIN INHIBITOR, IN HEALTHY MALE SUBJECTS, Stangier J., et al, Br J Clin Pharm, 64(3):292–303, September 2007
    AIMS: The novel direct thrombin inhibitor (DTI), dabigatran etexilate (Boehringer Ingelheim Pharma GmbH & Co. KG), shows potential as an oral antithrombotic agent. Two double-blind, randomized trials were undertaken to investigate the pharmacokinetics (PK), pharmacodynamics (PD) and tolerability of orally administered dabigatran etexilate in healthy male subjects. METHODS: Dabigatran etexilate or placebo was administered orally at single doses of 10–400 mg (n = 40) or at multiple doses of 50–400 mg three times daily for 6 days (n = 40). Plasma and urine samples were collected over time to determine the PK profile of dabigatran. PD activity was assessed by its effects on blood coagulation parameters: activated partial thromboplastin time (aPTT), prothrombin time (PT), reported as international normalized ratio (INR), thrombin time (TT), and ecarin clotting time (ECT). All adverse events were recorded. RESULTS: Dabigatran etexilate was rapidly absorbed with peak plasma concentrations of dabigatran reached within 2 h of administration. This was followed by a rapid distribution/elimination phase and a terminal phase, with associated estimated half-lives of 8–10 h and 14–17 h with single and multiple dose administrations, respectively. Dabigatran exhibited linear PK characteristics with dose-proportional increases observed in maximum plasma concentration and area under the curve. Steady-state conditions were reached within 3 days with multiple dosing. The mean apparent volume of distribution during the terminal phase (Vz/F) of 1860 l (range 1430–2400 l) and the apparent total clearance after oral administration (CLtot/F) of 2031 ml min-1 (range 1480–2430), were dose independent. Time curves for aPTT, INR, TT and ECT paralleled plasma concentration–time curves with values increasing rapidly and in a dose-dependent manner. At the highest dose of 400 mg administered three times daily, maximum prolongations over baseline of 3.1 (aPTT), 3.5 (INR), 29 (TT) and 9.5-fold (ECT) were observed. Dabigatran underwent conjugation with glucuronic acid to form pharmacologically active conjugates that accounted for approximately 20% of total dabigatran in plasma. Overall, variability in PK parameters was low to moderate, with an average interindividual coefficient of variation (CV) of approximately 30% and variability in PD parameters was low, with CV < 10%. Of the four assays, TT and ECT exhibited the greatest sensitivity and precision within the anticipated therapeutic dose range. Bleeding events were few and were mild-to-moderate in intensity, occurring only in the higher, multiple dose groups. CONCLUSIONS: These data suggest that dabigatran etexilate is a promising novel oral DTI with predictable PK and PD characteristics and good tolerability. Further investigation of dabigatran etexilate for the treatment and prophylaxis of patients with arterial and venous thromboembolic disorders, acute coronary syndromes and other medical conditions is warranted.

It is also noteworthy that in the PETRO study of 502 patients receiving dabigatran at 50, 150, or 300mg BID with aspirin, only the 300mg BID dosing schedule was associated with a higher risk of bleeding.

  1. DABIGATRAN WITH OR WITHOUT CONCOMITANT ASPIRIN COMPARED WITH WARFARIN ALONE IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION (PETRO STUDY) Ezekowitz, M.D., et al, 1;100(9):1419–26, Am J Card, November 2007 
    This is the first evaluation of dabigatran, an oral direct thrombin inhibitor, in patients with atrial fibrillation (AF). Patients (n = 502) were randomized to receive blinded doses of 50-, 150-, or 300-mg dabigatran twice daily alone or combined with 81- or 325-mg aspirin or open-label warfarin administered to achieve an international normalized ratio of 2 to 3 for 12 weeks. Dabigatran plasma concentrations, activated partial thromboplastin time, d-dimer, urinary 11-dehydrothromboxane B2 (DTB2), and liver function were measured at baseline and at 1, 2, 4, 8, and 12 weeks. Clinical end points were assessed according to the treatment received at the time of the event. Overall, 92% of patients completed the study. Major hemorrhages were limited to the group treated with 300-mg dabigatran plus aspirin (4 of 64), and the incidence was significant versus 300-mg dabigatran alone (0 of 105, p <0.02). Total bleeding events were more frequent in the 300-mg (39 of 169, 23%) and 150-mg (30 of 169, 18%) dabigatran groups compared with the 50-mg groups (7 of 107, 7%; p = 0.0002 and p = 0.01, respectively). Thromboembolic events were limited to the 50-mg dabigatran dose groups (2 of 107, 2%). The mean trough d-dimer measurements were suppressed for the 2 highest doses of dabigatran and warfarin (international normalized ratio of 2 to 3). Aminotransferase levels >3 times the upper limit of normal were observed in 0.9% of the dabigatran recipients and in none of the warfarin recipients. Two dabigatran recipients had aminotransferase levels >5 times the upper limit of normal as a result of gallstones, which resolved. Trough activated partial thromboplastin time values were 1.2, 1.5, and 1.8 times the baseline level for the 50-, 150-, and 300-mg dabigatran groups, respectively. DTB2 concentrations after 12 weeks of 50-, 150-, and 300-mg dabigatran treatment were increased by 31%, 17%, and 23%, respectively, versus baseline (p = 0.02, p = 0.03, and p = 0.0004). In conclusion, major bleeding events were limited to patients treated with dabigatran 300 mg plus aspirin and thromboembolic episodes were limited to the 50-mg dabigatran groups. The 2 highest doses of dabigatran suppress d-dimer concentrations. Serious liver toxicity was not seen. The significance of the increase of DTB2 concentrations in dabigatran-treated patients needs resolution.

QUESTION: WHAT IS THE ROLE OF LABORATORY TESTING IN DETERMINING THE EXTENT OF ANTICOAGULATION FROM DABIGATRAN?
Laboratory tests that can most reliably quantitatively detail the degree of anticoagulation are not readily available in most clinical laboratories. The thrombin time exhibits a linear dose response relationship to the plasma concentration of dabigatran, making it the most informative coagulation test. The ecarin clotting time provides similarly useful information. However, neither of these two tests is routinely available in clinical laboratories. Even if they were available, it is not clear how abnormalities in the times could be translated into clinically meaningful risk assessment tools. Of tests that are readily available, the aPTT (activated partial thromboplastin time) and INR can provide evidence of anticoagulation in patients who have ingested dabigatran though the degree of anticoagulation cannot be determined in a quantitative manner.

Recall that one effect of dabigatran is to impair the thrombin-mediated conversion of fibrinogen to fibrin. Dabigatran has effects on all the routine coagulation assays including the PT and aPTT. An increasing serum dabigatran concentration does result in increases in the aPTT but not in a linear manner and peak aPTT time plateaus at 2–3 times the control value (approximately 60 to 90 seconds) regardless of the serum dabigatran level. This means that in patients with acute overdose, the aPTT is likely to be similar to those who have simply ingested a therapeutic dose despite a markedly increased risk for hemorrhage. Note, however, that rises in the aPTT occur quickly in response to even subtherapeutic serum dabigatran levels, meaning that a normal aPTT is theoretically at least sensitive enough to rule out an anticoagulation state caused by dabigatran.

Similarly, the INR will most likely rise with both dabigatran use and overdose. Unfortunately the rise in INR is very slow compared to the plasma levels of dabigatran. In fact, INR appears to peak at approximately 2.0 despite very high plasma levels. Therefore, an elevated INR, like the aPTT, only qualitatively shows that the patient is experiencing anticoagulation but cannot reliably differentiate between therapeutic anticoagulation and severe anticoagulation. Importantly, and unlike the aPTT, the INR is not sensitive to the activity of dabigatran and a normal INR CANNOT be used to rule out significant dabigatran-induced anticoagulation. In short, a normal aPTT can rule out significant anticoagulation but a normal INR CANNOT. The bleeding time is not altered by dabigatran.

QUESTION: WHAT THERAPIES ARE AVAILABLE TO REVERSE DABIGATRAN-ASSOCIATED BLEEDING?
Dabigatran presents new challenges in the management of bleeding. There are extremely limited reversal agents that work in theory and even less experience dealing with bleeding problems associated with dabigatran use whether as a consequence of emergency surgery, therapeutic misadventure or toxic overdose. Management of overdose can be divided into three strategies 1) Supportive care (withholding further doses, avoiding agents that may exacerbate bleeding, giving packed cell transfusion and/or volume expansion, applying compression, using cautery, consulting with specialists who may assist in stopping the bleeding, etc…) 2) activating thrombin and 3) removing dabigatran.

The first point is self evident and will not be belabored. However, it should be emphasized that these supportive modalities are the ones that carry the most compelling theoretic benefits, because if the patient can be stabilized long enough for the drug to wear off (usually 6–12 hours), the patient may need no further treatment. Activating thrombin in the setting of dabigatran is challenging. FFP, the mainstay of therapy for warfarin-associated bleeding, is unlikely to help in this situation. FFP contains small amounts of prothrombin which may then be converted to thrombin and could overcome dabigatran inhibition. However, the amount of prothrombin in FFP is quite small and unlikely to reverse the effects of such a potent inhibitor, particularly in overdose. Recall that FFP works in warfarin overdose because warfarin is NOT an inhibitor but acts to cause a factor depletion state by impairing vitamin K metabolism and hence the synthesis of factor. Still FFP is readily available and does contain some prothrombin, and therefore could be used. Inactivated (using heparin or antithrombin) prothrombin complex concentrates (either 4 factor- KCentra, Briplex, Octaplex or 3 factor –Profilnine, Bebulin) offer more prothrombin compared with FFP and are, therefore, at least theoretically more useful for dabigatran-associated bleeding. A recent study of a murine intracranial hemorrhage model demonstrated PCC stabilized the dabigatran-associated bleed most effectively, but no human studies have proven effective to date.

Activated prothrombin complex concentrates (Feiba VH), which are generally used in hemophiliacs with inhibitors, offer a similar theoretic benefit to PCCs but have a higher reported incidence of producing a procoagulant effect. Activated recombinant Factor VIIa (Novoseven) is a potent procoagulant and general hemostatic agent that could be used, but poses a significant risk of causing thrombosis. It is important to note that there are no published case reports of strategies used to manage humans with dabigatran-associated bleeding. Cryoprecipitate is not expected to help in dabigatran-associated bleeding. Cryoprecipitate contains Factor VIII, vonWillibrand factor and fibrinogen, none of which are deficient with dabigatran use. Protamine sulfate, desmopressin, aprotinin, tranexamic acid and aminocaproic acid are not useful in dabigatran-associated bleeding.

QUESTION: CAN WE USE CHARCOAL OR HEMODIALYSIS IN THESE CASES?
Dabigatran binds well to charcoal, which, at least in theory, can be used to bind the drug if dabigatran ingestion was recent. Unfortunately, dabigatran is rapidly absorbed from the GI tract to the bloodstream limiting the utility of activated charcoal to the early ingestion phase. Further repeat charcoal is not indicated as there is no enterohepatic circulation. As dabigatran is not particularly protein bound, it can be dialyzed in the setting of severe bleeding. Dialysis removes approximated 62% of plasma dabigatran at 2 hours and 68% at 4 hours.

  1. DABIGATRAN ETEXILATE — A NOVEL, REVERSIBLE, ORAL DIRECT THROMBIN INHIBITOR: INTERPRETATION OF COAGULATION ASSAYS AND REVERSAL OF ANTICOAGULANT ACTIVITY, vanRyn J., et al, Thromb Haemost, 103(6):1116–27, June 2010. 
    Dabigatran etexilate is an oral, reversible direct thrombin inhibitor that is approved in the EU and several other countries for the prevention of venous thromboembolism after elective hip and knee replacement, and is in advanced clinical development for other thromboembolic disorders. Dabigatran has a predictable pharmacokinetic profile, allowing for a fixed-dose regimen without the need for routine coagulation monitoring. In certain clinical situations such as serious bleeding into critical organs (e.g. intracerebral bleeding), potential overdose and emergency surgery, clinicians will need to make an assessment of the anticoagulant status of a patient receiving dabigatran before deciding on future management strategies. If available, thrombin clotting time (TT), ecarin clotting time (ECT) and TT determined by Hemoclot thrombin inhibitor assay are sensitive tests to evaluate the anticoagulant effects of dabigatran. Prothrombin time (INR) is less sensitive than other assays and cannot be recommended. The activated partial thromboplastin time (aPTT) can provide a useful qualitative assessment of anticoagulant activity but is less sensitive at supratherapeutic dabigatran levels. There are limited data for activated clotting time (ACT). Overall, the aPTT and TT are the most accessible qualitative methods for determining the presence or absence of anticoagulant effect. Although there is no specific antidote to antagonize the anticoagulant effect of dabigatran, due to its short duration of effect drug discontinuation is usually sufficient to reverse any excessive anticoagulant activity. In case of potential overdose, the feasibility of early administration of activated charcoal and subsequent charcoal filtration are undergoing preclinical evaluation. Dabigatran can also be dialyzed in patients with renal impairment. In instances of life-threatening bleeding, where conventional measures have failed or are unavailable, other non-specific prohaemostatic agents such as recombinant activated factor VII and prothrombin complex concentrates can be considered.
  2. DABIGATRAN: REVIEW OF PHARMACOLOGY AND MANAGEMENT OF BLEEDING COMPLICATIONS OF THIS NOVEL ORAL ANTICOAGULANT, Ganetsky, M, et al, .J Med Toxicol,. September 2. 2011
    Dabigatran (Pradaxa) is a competitive direct thrombin inhibitor approved by the US FDA for prevention of embolic stroke in patients with nonvalvular atrial fibrillation. Dabigatran has a pharmacokinetic profile that produces predictable anticoagulation responses, does not undergo CYP 450 metabolism, has few drug-drug and drug-food interactions, and does not require frequent laboratory monitoring of clotting parameters. Clinicians are rapidly prescribing this agent as a replacement for warfarin therapy. However, no therapeutic agent has been accepted to reliably reverse the hemorrhagic complications of dabigatran. As of yet, there is no solid evidence to guide management of bleeding complications; management should start with local control of bleeding when possible and transfusion of pRBCs if needed. Transfusion of FFP would not be expected to help control bleeding. Limited and mixed data exist for transfusion of factor VIIa and prothrombin complex concentrates; these therapies should be considered as well as dialysis, which will increase elimination in patients with life-threatening or closed-space bleeding due to dabigatran. We present an article that reviews the pharmacokinetics, clinical trial literature, and consensus guidelines regarding this novel oral anticoagulant.

QUESTION: WHAT SHOULD BE THE APPROACH TO TREATING THE BLEEDING PATIENT ON DABIGATRAN?
Until further studies address the best method to treat patients on dabigatran who are bleeding, the approach to severe or life-threatening bleeding in patients on this agent should be:

  • Withhold additional doses of dabigatran
  • Avoid other agents that may exacerbate bleeding (NSAIDs, ASA, etc.)
  • Supportive measures (pRBCs, IV fluids, direct pressure, cautery, consultation as indicated, etc.)
  • Consider activated charcoal if the dabigatran was taken within 1–2 hours
  • Consider administering 4-factor PCCs
  • Consider dialysis

QUESTION: WHAT ARE THE “XABANS” AND HOW DO THEY INHIBIT COAGULATION?
The “xabans” (“xa” for blocking Factor “Xa”) are oral factor Xa inhibitors that prevent the conversion of prothrombin to thrombin, acting near the end of the common pathway in the coagulation cascade. The two xabans available in the U.S. are approved for prophylaxis of DVT in patients undergoing orthopedic surgery and to reduce stroke risk in patients with nonvalvular atrial fibrillation. Rivaroxaban is also approved for the treatment of DVT and PE. Like dabigatran, xabans are NOT indicated for anticoagulation in patients with mechanical valves.

Like the direct thrombin inhibitors, treatment of excessive anticoagulation is very problematic. Although Factor Xa inhibitor antidotes are in development and could prove to be useful for patients on these agents who are bleeding, they are not currently available. Also, like dabigatran, the anticoagulant effect of these agents cannot be reliably measured by routinely available coagulation testing (although a factor Xa test is in development).

The most recent trial of apixaban (ARISTOTLE) has been heralded as a major breakthrough in the treatment of nonvalvular atrial fibrillation and, if an antidote is able to be produced to counter the effects of the “xabans,” it is likely that this drug will replace dabigatran (which has had a slow start in being adopted).

  1. 8. APIXABAN VERSUS WARFARIN IN PATIENTS WITH ATRIAL FIBRILLATION, Granger, C., et al, NEJM, 365:981, September 15, 2011
    BACKGROUND: Vitamin K antagonists are highly effective in preventing stroke in patients with atrial fibrillation but have several limitations. Apixaban is a novel oral direct factor Xa inhibitor that has been shown to reduce the risk of stroke in a similar population in comparison with aspirin. METHODS: In this randomized, double-blind trial, we compared apixaban (at a dose of 5 mg twice daily) with warfarin (target international normalized ratio, 2.0 to 3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. The primary outcome was ischemic or hemorrhagic stroke or systemic embolism. The trial was designed to test for noninferiority, with key secondary objectives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause. RESULTS: The median duration of follow-up was 1.8 years. The rate of the primary outcome was 1.27% per year in the apixaban group, as compared with 1.60% per year in the warfarin group (hazard ratio with apixaban, 0.79; 95% confidence interval [CI], 0.66 to 0.95; P<0.001 for noninferiority; P=0.01 for superiority). The rate of major bleeding was 2.13% per year in the apixaban group, as compared with 3.09% per year in the warfarin group (hazard ratio, 0.69; 95% CI, 0.60 to 0.80; P<0.001), and the rates of death from any cause were 3.52% and 3.94%, respectively (hazard ratio, 0.89; 95% CI, 0.80 to 0.99; P=0.047). The rate of hemorrhagic stroke was 0.24% per year in the apixaban group, as compared with 0.47% per year in the warfarin group (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; P<0.001), and the rate of ischemic or uncertain type of stroke was 0.97% per year in the apixaban group and 1.05% per year in the warfarin group (hazard ratio, 0.92; 95% CI, 0.74 to 1.13; P=0.42). CONCLUSIONS: In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality. (Funded by Bristol-Myers Squibb and Pfizer; ARISTOTLE ClinicalTrials.gov number, NCT00412984.)

Although they have only been on the market for a couple of years, the new “xabans” have already had several black box warnings issued. The first addresses the risk of neurological impairment with “neuroaxial intervention.” Basically, any intervention that enters the dural space may cause an epidural hematoma in patients on xabans. Emergency physicians need to be aware of this risk when considering doing a lumbar puncture in these patients and should consider this procedure contraindicated until it is clear the anticoagulant effect of the drug has worn off.

The second black box deals with the risk of thromboembolism when doses of the drug are missed or when it is discontinued. The warning reads “Premature discontinuation of apixaban increases the risk for thrombotic events.” This includes both stroke and systemic thrombotic events. While the risk of missing a single dose of the agent is unclear, emergency physicians should be aware of this concern and need to assure that patients do not inadvertently miss doses while boarding in the emergency department waiting for a hospital bed.

QUESTION: WHAT SHOULD BE THE APPROACH TO TREATING THE BLEEDING PATIENT ON A XABAN?
Treatment of bleeding patients on xabans is similar to that in patients on dabigatran with the exception of dialysis, as the xabans are highly protein bound and therefore not dialyzable. The prothrombin complex concentrates may be more effective for treating bleeding in patients on xabans. Until a more specific antidote for factor Xa blockage is developed and tested, use of a 4-factor PCC appears to be the best treatment at this time.

QUESTION: WHAT IS THE CONSENSUS OF EXPERT OPINION REGARDING THE TREATMENT OF PATIENTS WHO ARE BLEEDING WHILE ON THE NEW ORAL ANTICOAGULANTS?
In December of 2011 representatives from 10 organizations that focus on thrombosis and anticoagulation convened a meeting to collaboratively develop pragmatic guidance for clinicians to manage the reversal of these new agents until more definitive and evidence-based guidelines become available. Their recommendations were published in the American Journal of Hematology, May 2012 as part of a supplement. They mirror the advice noted previously in this presentation.

  1. Supportive care: Patients treated with apixaban, dabigatran, or rivaroxaban who present with significant bleeding or the need for emergent surgery should receive routine usual supportive care including fluid resuscitation, red blood cell transfusions, maintenance of renal function, identification of bleeding source, and surgical intervention as needed.
  2. Discontinuation of drug: Given the relatively short half-lives of the new oral anticoagulants, withholding further doses and supportive care is likely to be sufficient for many patients. In patients with normal renal function, most of the anticoagulant effect of the new medications should dissipate within a day or two.
  3. Activated charcoal: If oral drug intake was within a couple of hours of presentation, oral activated charcoal offers a low side effect treatment option.
  4. Hemodialysis and hemoperfusion: The pragmatic barriers to initiating emergent dialysis often impede the practicality of this therapy. This intervention will likely remove 2/3 of dabigatran within a couple of hours. It should be considered, especially in patients with impaired renal function who will require more time to clear the drug. Use of dialysis is not likely to be effective for apixaban or rivaroxaban, as they are highly protein bound.
  5. FFP: In our opinion, FFP is not likely to be helpful for emergent reversal of the new oral anticoagulants. The use of FFP has only been evaluated for dabigatran in a mouse model using species-specific plasma. The use of human FFP in patients has not been studied. Additionally, reversal of the new anticoagulants with FFP would require overwhelming the direct effect of the drugs either on factor IIa or Xa, not merely replacing depleted factor concentration as in the case of reversal of VKAs.
  6. The use of factor VIIa in nonhemophiliac patients is associated with an increase in arterial thrombosis. Human rVIIa decreases the bleeding time in rats that have been given dabigatran or rivaroxaban; however, it does not reverse the anticoagulation effect as measured by most laboratory tests in this model. There have been no human studies to date and it is unclear if this therapy will be useful for emergent anticoagulation reversal.
  7. PCC: The use of either 3-factor or 4-factor PCCs has the potential to increase the risk of thrombosis. One nonactivated 4-factor PCC has been shown to normalize the PT in human volunteers who received rivaroxaban, but did not normalize the aPTT or thrombin time in subjects who received dabigatran. There have been no studies evaluating the effect of PCCs on bleeding in humans receiving the new oral anticoagulants. Whether use of PCCs will be effective to stop critical bleeding or reverse the anticoagulant effects of the new agents enough to safely proceed with emergent surgery is not established but seems, given the current state of information, to be a reasonable approach in dire clinical situations in the opinion of several of the authors. Importantly, however, consensus was not reached regarding PCC, as two authors felt that PCC cannot be recommended at this time due to absence of data. All authors agreed that an equally justifiable approach, based on the current level of information, is to continue with supportive care and local measures to arrest bleeding.

KEY POINTS AND RECOMMENDATIONS

  1. Dabigatran inhibits coagulation by directly inhibiting thrombin and, as such, works substantially differently than warfarin.
  2. Because thrombin is not on either the intrinsic nor extrinsic pathways of the coagulation cascade, routine coagulation studies do not reliably predict the extent of anticoagulation induced by dabigatran.
  3. Dabigatran causes the aPTT to become abnormal — but the magnitude of anticoagulation is not able to be ascertained.
  4. A normal prothrombin time does not, however, exclude the presence of dabigatran nor the amount or degree of anticoagulation induced.
  5. Factor Xa inhibitors also cause unpredictable changes in routine coagulation studies for reasons similar to those for the direct thrombin inhibitors.
  6. Treatment of bleeding due to the thrombin inhibitors and Factor Xa inhibitors is very problematic since current treatments used for warfarin-induced bleeding are not particularly effective.
  7. Reversal of direct thrombin inhibitors theoretically should respond to prothrombin and, as such, prothrombin complex concentrates may be the most effective therapy, but evidence is lacking.
  8. Removal by dialysis is an option in the bleeding patient on dabigatran.
  9. Development of an antidote to the Factor Xa inhibitors has the potential to make this class of drugs preferred to the thrombin inhibitors.
  10. Use of these drugs in a variety of clinical settings is being studied extensively

Chapter Authors:

Michael Menchine, M.D., M.P.H
Associate Professor of Emergency Medicine 
Chief of Clinical Research
Department of Emergency Medicine
Keck School of Medicine of USC 
Los Angeles, CA

Diane M. Birnbaumer, M.D., FACEP
Professor of Medicine
David Geffen School of Medicine at UCLA
Senior Clinical Educator
Department of Emergency Medicine
Harbor-UCLA Medical Center
Los Angeles, California