Emergency physicians frequently need to manage severe bleeding associated with vitamin-K antagonists (VKAs, eg. warfarin). Most of us are comfortable with the appropriate dosing of fresh frozen plasma (FFP) and vitamin K, as well as the general bleeding control measures that are needed for the intracerebral hemorrhages (ICHs), gastrointestinal bleeds (GIBs) and other major bleeding events in these anticoagulated patients.
NOACs offer promise as alternatives to warfarin. But when patients present with bleeding in the ED, it’s essential you know the critical differences between them.
Emergency physicians frequently need to manage severe bleeding associated with vitamin-K antagonists (VKAs, eg. warfarin). Most of us are comfortable with the appropriate dosing of fresh frozen plasma (FFP) and vitamin K, as well as the general bleeding control measures that are needed for the intracerebral hemorrhages (ICHs), gastrointestinal bleeds (GIBs) and other major bleeding events in these anticoagulated patients. However, in the last few years, several novel oral anticoagulants (NOACs) and potential antidotes have entered the marketplace, offering the promise of simplified anticoagulation and reversal. Their use has also complicated the management of severe anticoagulant-associated hemorrhage.
The NOACs are a heterogeneous group of oral anticoagulants comprised of the direct thrombin inhibitor (DTI) dabigatran (Pradaxa) and the factor Xa inhibitors rivaroxiban (Xarelto) and apixiban (Eliquis). Endoxaban, a Xa inhibitor approved in Japan, is likely to gain FDA approval due to similar efficacy [1]. Unlike warfarin, which reduces the circulating levels of vitamin K-dependent clotting factors by inhibiting their production, these agents directly antagonize the action of normal levels of circulating clotting factors. This difference in their mechanism of action explains why traditional tools for VKA reversal, such as FFP and vitamin K, are ineffective in reversing NOACs.
While the site of action of the DTI dabigatran is distal to that of the two currently FDA-approved factor Xa inhibitors, both classes of agents are delivered in oral formulations and share important pharmacological similarities. Compared to warfarin, all have a very rapid times to peak action – only two to three hours – and short biological half-lives of 6-15 hours (table on page 15).
The DTIs and factor Xa inhibitors both have high rates of renal excretion, although the rate is higher for dabigatran (80% renally cleared, all unchanged) compared to the factor Xa inhibitors (66% renally cleared, 33% unchanged). However, one key difference between the classes of agents does deserve mention: the factor Xa inhibitors are highly protein bound, while dabigatran is only 35% protein bound. This makes hemodialysis a realistic option for reversal of dabigatran, particularly in cases of overdose.
Who bleeds, and where
The patients presenting to the ED with major bleeding on the NOACs are likely to be the same patients that currently present with warfarin-associated bleeding. The NOACs were designed and FDA approved (and are currently marketed) as convenient warfarin replacements for specific patients. Dabigatran and rivaroxaban are currently FDA approved for non-valvular atrial fibrillation and DVT/PE, while apixaban is approved only for non-vascular atrial fibrillation. These agents have been shown in large randomized controlled trials to be non-inferior to warfarin for these indications[2-4]. Industry marketing touts the lack of food and medication interactions of these agents which, combined with their wide therapeutic ranges, obviates the need for frequent monitoring.
As with warfarin, the major complication of the NOACs is bleeding, which can often be life-threatening. Overall rates of major bleeding and mortality appear to be similar between both NOACs and warfarin; however their risk factors and sites of bleeding appear to differ. For example, elderly patients and those patients who develop renal failure while taking dabigatran are at greater risk for bleeding, and this is more often gastrointestinal bleeding (GIB) and less often intracerebral hemorrhage (ICH) than similar patients taking warfarin [5, 6].
What to ask – and order
The ED evaluation of patients with bleeding who are taking NOACs is similar to the evaluation of patients taking warfarin, with a few notable exceptions. Critical differences include asking about the timing and dose of their last NOAC and any history, signs or symptoms that raise the suspicion for decreased renal function. Be sure to ask about fluid intake, urine output and use of nephrotoxins, particularly NSAIDs. Physical examination should include a reduced threshold for stool guaiac testing due to the increased risk for GIB. Patients should also have their serum creatinine measured as a surrogate for normal NOAC metabolism and clearance and these patients anticipated to have ongoing bleeding should have standard hematocrit, platelet counts, and blood type measured in anticipation of potential blood transfusion.
In terms of coagulation studies, the current and readably available generation of laboratory studies are inadequate to determine the effect (and by extension concentration) of circulating NOACs. Prothrombin time (PT) and activated partial thromboplastin time (PTT) are rather adept for following warfarin and heparin, respectively; however these tests lack sensitivity and specificity for NOAC management. The preferred testing methods for dabigatran activity are thrombin time (TT), hemoclot test or Ecarin clotting time, and anti-factor Xa testing is preferred for rivaroxaban and apixaban.
However, there is some value in PT/PTT evaluation in the evaluation and management of patients with significant hemorrhage while taking NOACs, so long as the general trends and limitations of the results are understood (see table). Dabigatran tends to produce major elevations in PTT and minor elevations in PT, while the factor Xa inhibitors tend to produce minor elevations in both assays [7, 8]. There is data to support the idea that normal levels of PT and PTT virtually exclude the presence of clinically significant levels of either dabigatran or rivaroxaban and we do recommend targeting reversal of these agents with 4-factor prothrombin complex concentrate (PCC) to normalization of these assays (see below) [9, 10]. However, emergency physicians should be cautious, as this is not a well-studied area and there are reports of patients with therapeutic levels of dabigatran and normal PT and PTT levels [11].
Indications for imaging of patients with actual or suspected NOAC-associated bleeding should closely mirror the approach for patients with bleeding with warfarin. As there are no well-validated decision rules to guide the use of imaging in patients taking these anticoagulants, we tend to liberally image patients with suspected hemorrhage, especially in the setting of trauma.
Managing the bleed
The management of NOAC-associated bleeding is poorly informed by the current literature. The development and release of these medications has eclipsed the research into their safe reversal. This uncertainty, combined with their relatively brief half-lives, underscores the need for prevention of bleeding and aggressive supportive care. General site-specific approaches should be used, such as direct pressure or tourniquets for extremity hemorrhage and aggressive blood pressure control for ICH. Physicians should expect theoretically decreased function of hemostatic trauma gauze preparations, as these agents tend to activate clotting factors upstream of NOAC-mediated inhibition.
In terms of specific therapy for NOAC-associated bleeding, there is the potential for clinical success with recombinant or purified clotting factor preparations, such as PCCs, Factor VII inhibitor bypass activity (FEIBA), recombinant factor VIIIa (rVIIa), or some combination of these agents.
However, many of these agents have high rates of complications, particularly the arterial and venous thromboses seen with FEIBA and rVIIa. These two agents should generally only be given in cases of severe or life-threatening hemorrhage and after discussion with a hematologist. PCCs, while potentially effective for Xa-inhibitor mediated bleeding, are costly. Although exact costs are difficult to obtain, there is approximately a five to ten-fold difference between FFP and PCCs at our home institution. However, in cases of severe bleeding in patients on NOACs, FFP should only be given if it is the only available therapy; concentrations of clotting factors in FFP are much lower than those of PCCs when reasonable starting doses are compared (Table 2). Furthermore, initial and repeat dosing of PCCs is facilitated by the relatively small volumes infused and lack of type-specificity, making factor delivery much faster and safer, particularly in patients for whom large volume infusions may not be well tolerated.
In the case of true life-threatening bleeding on rivaroxaban, the use of 4-factor PCC may be considered based on small healthy volunteer and ex vivo studies [12, 13]. The effect of 4-factor PCC to reverse dabigatran is likely to be negligible in comparison to the effect on the Xa inhibitors, based on the currently available data. Regardless, any reversal should be evaluated with standard coagulation studies performed 30 minutes after PCC infusion with the target of normalization of these laboratory markers. The approximate rate of thrombosis with 4-factor PCC is 3.9%, as compared to 2.8% for plasma (non-significant difference), however this has only been studied in the setting of warfarin reversal[14].
Who to call for help
The effective and appropriate use of consultants is an essential part of the team-based approach we recommend for major NOAC-associated bleeding. Early consultation of a hematologist, when available, is appropriate in any case of planned reversal or severe bleeding in patients taking NOACs. Furthermore, a nephrologist may be of assistance for the consideration of hemodialysis in patients with bleeding on dabigatran in the setting of overdose or poor renal function. Consultation with the patient’s prescribing physician may be appropriate to discuss plans to prevent complications following reversal of their anticoagulation. However, the FDA-approved indications for use of NOACs specifically exclude high-risk groups such as patients with vascular stents or mechanical cardiac valves. For this reason, short-term reversal should be uncomplicated for patients on NOACs for FDA-approved indications.
Following initial ED evaluation and management, disposition should be based on the physician’s assessment of the patient’s current bleeding status and response to therapy. While the short half-life of the NOACs is enticing, our practice is to admit the overwhelming majority of these patients unless the bleeding has been completely controlled. It will likely continue to be such until studies develop that can guide the identification of the subset of patients who are safe to discharge home.
References
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2. Connolly, S.J., et al., Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med, 2009. 361(12): p. 1139-51.
3. Patel, M.R., et al., Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med, 2011. 365(10): p. 883-91.
4. Granger, C.B., et al., Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med, 2011. 365(11): p. 981-92.
5. Berger, R., et al., Hemorrhagic complications in emergency department patients who are receiving dabigatran compared with warfarin. Ann Emerg Med, 2013. 61(4): p. 475-9.
6. Harper, P., L. Young, and E. Merriman, Bleeding risk with dabigatran in the frail elderly. N Engl J Med, 2012. 366(9): p. 864-6.
7. Alikhan, R., et al., The acute management of haemorrhage, surgery and overdose in patients receiving dabigatran. Emerg Med J, 2013.
8. Godier, A., et al., Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology, 2012. 116(1): p. 94-102.
9. Dager, W.E., et al., Dabigatran effects on the international normalized ratio, activated partial thromboplastin time, thrombin time, and fibrinogen: a multicenter, in vitro study. Ann Pharmacother, 2012. 46(12): p. 1627-36.
10. Steiner, T., et al., Recommendations for the emergency management of complications associated with the new direct oral anticoagulants (DOACs), apixaban, dabigatran and rivaroxaban. Clin Res Cardiol, 2013. 102(6): p. 399-412.
11. Hawes, E.M., et al., Performance of coagulation tests in patients on therapeutic doses of dabigatran: a cross-sectional pharmacodynamic study based on peak and trough plasma levels. J Thromb Haemost, 2013. 11(8): p. 1493-502.
12. Eerenberg, E.S., et al., Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation, 2011. 124(14): p. 1573-9.
13. Marlu, R., et al., Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost, 2012. 108(2): p. 217-24.
14. Sarode, R., et al., Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation, 2013. 128(11): p. 1234-43.