Thank you Dr. Kaltman for the excellent post.
NOACs, otherwise known as Target Specific Oral Anticoagulants (TSOACs), have been gaining more traction for use due to their ease of dosing, lack of drug-drug and drug-food interactions, and reduced requirements for monitoring. The two main mechanisms of action for TSOACs are either 1) inhibition of Factor II (Direct Thrombin Inhibitor; DTI), or 2) Factor Xa inhibitors (FXAi).
Until recently, drawbacks of using these non-vitamin K antagonist anticoagulants included a difficulty in determining the degree of anticoagulation present, and a lack of a binding or reversal agent.
The following information should be considered in a patient on a TSOAC that presents with bleeding who may require urgent anticoagulation reversal:
- Location and degree of bleeding severity
- Timing of last TSOAC ingestion
- Presence of renal and/or hepatic dysfunction
- Attainment and interpretation of coagulation parameters
- Awareness of reversal options
Before considering the reversal of anticoagulation, the benefits versus risks must be weighed. In an obvious case where reversal is indicated (intracerberal hemorrhage, intra-abdominal bleeding with hypotension, or any life threatening bleed requiring emergent intervention), the administration of reversal agents or antidotes should not be delayed. However, when a patient presents with a less critical bleed (such as a calf hematoma) and is hemodynamically stable, the decision to reverse becomes more complicated. Reversal carries a significant risk of thrombosis (thrombotic risk: rFVIIa = FEIBA > Kcentra). Thrombotic risk may be lower with the use of monoclonal antibodies (idarucizumab, andexanet alfa, ciraparantag), however their true safety and efficacy is still under question. Regardless, sudden discontinuation of a TSOAC may predispose the patient to an increased risk of thrombosis as a rebound phenomenon.
If possible, the time that the last dose of the TSOACs was taken should be ascertained. This is important for two reasons: it may affect the dose of reversal agent, and it may assist in interpreting the associated coagulation parameters for drug accumulation versus an aberrant expected degree of anticoagulation.
Upon patient presentation, a CBC, chemistry panel, LFTs, and coagulation tests should be ordered. Acute kidney injury and/or liver injury should raise concern for TSOAC accumulation and may correlate with grossly elevated coagulation parameters. The TSOACs vary in their primary routes of elimination. Dabigatran is exclusively renally eliminated, whereas rivaroxaban is 40% eliminated via the kidneys (50% via multiple hepatic pathways and 10% via feces) and apixaban is about 25% eliminated via the kidneys (10% via feces and the remainder via the liver). Edoxaban is 50% renally eliminated and the remainder is via biliary and intestinal excretion.
Therefore, it is important to know what is the optimal test for interpreting the coagulation status of these patients (as well as the tests’ turn around time for results). Unfortunately, this is not as simple as it seems. Depending on the serum concentration of these agents (due to recent ingestion vs. accumulation secondary to renal and/or liver dysfunction), coagulation tests can be difficult to interpret in a traditional sense.
Here is a summary of the common coagulation tests that may assist in detecting presence and/or degree of a TSOAC affecting coagulation:
- Dabigatran: the most sensitive test for the presence of dabigatran is the Thrombin Time (TT). Although aPTT and PT/INR may assist in identifying the presence of dabigatran, it cannot be relied on for its exclusion. On the other hand, a normal TT would indicate there is no dabigatran present. An elevated TT doesn’t necessarily correlate with acertain degree of anticoagulation. The turnaround time for TT is 1-2 hours, which could pose a delay in care compared to point-of-care testing of a PT/INR.
- Apixaban, rivaroxaban, and edoxaban: If available, a standardized Anti-Xa assay specific for the individual anti-Factor Xa inhibitor should be used for identifying and quantifying the anticoagulant. At our institution, we have Anti-Xa assays for apixaban, dalteparin, enoxaparin, fondaparinux, and rivaroxaban but not edoxaban. Similar to the TT, the turnaround time is also 1-2 hours. However, if the specific anti-Factor Xa assay is unavailable, the PT/INR could be used to screen patients receiving rivaroxaban (with similar limitations as with dabigatran), but not with apixaban.
The options available for correction of excessive anticoagulation are stratified into two broad categories: 1) reversal agents, and 2) binding agents.
Reversal agents are medications that counteract the effects of the anticoagulant. Four Factor Prothrombin Complex Concentrate (4FPCC) is the agent of choice, and it is further broken down into two agents, FEIBA (activated-4FPCC) and Kcentra (4FPCC). NovoSeven (rFVIIa) has no role in these circumstances and should not be used. Prior to Kcentra’s introduction to the US market, FEIBA was the sole option available to reverse TSOACs in emergent situations. Since FEIBA is activated, it has the propensity to be particularly thrombogenic, causing strokes, MIs, or VTEs. Kcentra’s subsequent FDA approval led to additional investigation of its role in TSOAC reversal. It has been shown that Kcentra is effective in the reversal of Factor Xa inhibitors but not for DTIs, therefore FEIBA should only be used for the reversal of dabigatran. This is because FEIBA carries a higher risk of thrombosis with no apparent benefit over Kcentra in the reversal of Factor Xa inhibitors.
Optimal dosing of these reversal agents is still unclear, however, larger doses may not provide any additional benefit that would outweigh the increased thrombosis risk. Similarly, the role of repeated lower doses based on coagulation factor trending and hemostasis control remains a controversial, yet alternate approach. It is essential for your institution to develop a protocol to assist in facilitating care in these situations.
With the advent of monoclonal antibodies, known as “binding agents,” clinicians have a new and potentially safer option for reversing TSOACs. It is imperative to scrutinize these studies closely to understand their true safety and efficacy.
Before idarucizumab (Praxbind) (a monoclonal antibody fragment), there were only two options for clearing dabigatran: either be courageous enough to place a vascath line for dialysis, or administer FEIBA and hope that you won’t cause an MI or a stroke. The emergence of idarucizumab on the market was potentially life saving, as it has a binding affinity 350 times greater for dabigatran than dabigatran has to thrombin. However, the process of how idarucizumab ended up on the market deserves a closer look.
The first study of idarucizumab was a “safety” study that showed there were no side effects, i.e. thrombotic events. This was followed by a second study (Phase I) in which healthy volunteers were loaded with dabigatran and reversed with idarucizumab, demonstrating the effective reversal of various coagulation indicators (dTT, ECT, aPTT and TT) (PMID 26088268). It is important to note that this was a dose finding and safety study, rather than a clinical efficacy study.
This paved the way for the REVERSE-AD study (PMID 26095746) from which the FDA granted idarucizumab approval for use. This is a multicenter international prospective (still) ongoing study that published interim results after enrolling 90 patients reported to take dabigatran who presented with signs of life threatening bleeding and/or for emergent surgery requiring anticoagulation reversal. For the FDA approval, the study’s primary endpoint was the maximal correction of dTT and ECT within 4 hours of second infusion. Secondary endpoints were time to bleeding cessation, bleeding occurrence up to 24 hours post surgery, and free dabigatran levels.
Idarucizumab reversed 100% of patients at the 4 hour mark (measuring dTT and ECT), but this is simply an examination of laboratory values. As for other essential indicators of hemostasis, the median time to cessation of bleeding was 11.4 hours, and 5 out of 90 patients experienced thrombotic events. Idarucizumab corrected “numbers,” but the time until cessation of bleeding indicates a prolonged time until truly achieving hemostasis control. The half-life of dabigatran is approximately 8-14 hours in patients with normal renal function and up to 28 hours in renal dysfunction. Therefore, was hemostasis due to idarucizumab administration, or due to excretion of dabigatran itself? Another interesting finding was that a nadir in dabigatran levels was attained at 4 hours post infusion, with a subsequent rise. Was this due to redistribution of dabigatran from the extravascular space back intravascularly, and what does this mean clinically? Should idarucizumab be redosed or given as a longer infusion in those that present with an AKI, and would this be safe to do? These questions remain unanswered for now.
Limitations to this study are the “reported” use of dabigatran, classification of surgery (some of the procedures are considered noninvasive), lack of control group, small sample size, concern for selection bias, and the fact that ~25% of patients enrolled subsequently had normal ECT and dTT values. Additionally, Boehringer Ingelheim, the manufacturer of dabigatran itself, assisted in study design, analysis and sponsorship, potentially introducing bias.
Until more patients are enrolled with a better defined clinical endpoint (ie, rather than just numerical laboratory endpoints with limited safety data), this study’s results should be viewed with caution. Idarucizumab can be used as labeled, but understand it is not the “magic bullet” we were hoping for.
Another agent for reversal under investigation is andexanet alfa (recombinant modified human Factor Xa decoy protein), the antidote for the FXAis, under the ANNEXA-4 trial (PMID: 27573206) which followed the ANNEXA-A/R trials (PMID 26559317). The authors reported interim results on 67 patients (47 for efficacy analysis) given andexanet alpha in the setting of a life-threatening bleed. Similar to the REVERSE-AD study, this study is ongoing, and the study’s methodology is fraught with flaws (including a small number of non-blinded patients, the exclusion of higher acuity patients, and a vague clinical endpoint). Thus, it seems that the ANNEXA trial is shaping up to be another PK/PD study. The coprimary endpoints are the percent change in the Anti-Xa levels, and “good or excellent” hemostatic efficacy 12 hours post-infusion. Safety endpoints are death or a thrombotic event at thirty days. How “good or excellent” hemostatic efficacy is defined is through a complicated multi-step process of determining clinical outcomes.
As for the results, about half the patients who received the antidote were receiving rivaroxaban or apixiban, with only one patient receiving enoxaparin and no patients were receiving edoxaban. It took almost 5 hours to start andexanet from ED presentation, which may highlight the degree of “patient acuity” included in the study. Upon the receipt of the bolus dose, there was a 90% relative decrease in Anti-Xa and was maintained (85-90% decrease) by the end of the 2 hour infusion. Anti-Xa levels rose up to a relative decrease of 30-40% four hours after the conclusion of the second infusion. Regarding clinical efficacy, authors reported that 84% and 80% of patients achieved excellent or good hemostasis 12 hours after the end of infusion, respectively.
Regarding the safety profile, about 20% of patients had a thrombotic event within 30 days. Similar to idarucizumab, it seems that andexanet alfa “corrects” numbers, but how does this translate to clinical outcomes? Many of the limitations discussed regarding idarucizumab above also applies to this study as well.
And finally, ciraparantag is a universal reversal agent for DTIs, FXAis and heparin molecules. Ciraparantag is currently in Phase II studies, and its claim to fame is that there will be no rebound anticoagulation with minimal thrombotic adverse events. It is reported to be the “king” of monoclonal antibodies. For now… I’m going to hold my breath and hope that at least this time, we have a well-designed study with meaningful clinical endpoints that we could apply to our next TSOAC bleeding patient.
So, where do we go from here? We are still a long way from having our “magic bullet” for the reversal of TSOACs. However, our currently available binding and reversal agents serve as a viable option for those with severe bleeding requiring reversal. Clinicians should be aware of the numerous limitations and the lack of a pragmatic measurable endpoint related to the monoclonal antibodies. For now, if a patient presented with a life-threatening bleed, a monoclonal antibody may be preferable to use, and may be safer than 4FPCCs. However, it is prudent to closely monitor patients for greater than 48 hours, and perhaps longer when the patient has an AKI. There are many important unanswered questions regarding monoclonal antibody use, and trial design and endpoints leave much to be desired when applying the data to everyday clinical practice. I would be cautious in interpreting preliminary results but excited to what the future holds for these binding agents.
Thank you for reading!
Ahmed Mahmoud, PharmD, BCCCP
ICU and ED Clinical Pharmacist, Northwestern Memorial Hospital
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How to cite this blog post:
[Peer-Reviewed, Web Publication] Kaltman D, Li S (2017, February 21). Reversal of Novel Anticoagulants [NUEM Blog. Expert Commentary By Mahmoud A]. Retrieved from http://www.nuemblog.com/blog/noac-reversal