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My Take on Compelling Audience Questions From the Management of Anticoagulant-Related Major Bleeding: Clinical Updates and Best Practices for Health-System Pharmacists

Tyree H. Kiser, PharmD, FCCP, FCCM, BCCCP, BCPS

University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences
University of Colorado Anschutz Medical Campus
Clinical Pharmacy Specialist – Critical Care
University of Colorado Hospital
Aurora, Colorado

Tyree H. Kiser, PharmD, FCCP, FCCM, BCCCP, BCPS, has no relevant conflicts of interest to report.

View ClinicalThoughts from this Author

Released: December 30, 2021

In this commentary, I answer audience questions about oral anticoagulant reversal from the live webinar, “Management of Anticoagulant-Related Major Bleeding: Clinical Updates and Best Practices for Health-System Pharmacists.”

Can you use thromboelastography (TEG) to predict outcome of reversal?

At the University of Colorado Hospital, we use TEG frequently, and we just published data looking at TEGs and some of our factor Xa assessments. Looking mostly at the R time, the time to initial clot formation, the data were not as clear as we had hoped it would be. We used it mostly up-front to see what sort of reversal strategy and/or agents we might give the patient if potential platelet function or other issues were driving the R time rather than just a single anticoagulant. We have performed TEGs after giving a reversal agent, and particularly in patients who have ended up going to the operating room, we have occasionally used TEGs to follow them during the surgical procedure. We have seen some improvements in some of the R time but have not found it useful to gauge whether to give more, for example, prothrombin complex concentrate to the patient and whether that would actually affect outcome.

I am excited about the potential for TEGs, but at this point, I am not certain we fully understand the accuracy of the data.

There’s some evidence correlating anti–factor Xa levels calibrated for heparin or enoxaparin to direct oral anticoagulants (DOAC) concentrations to estimate when a patient has nonclinically significant DOAC concentrations in candidates for neurosurgery. What are your thoughts?

We have done that at our institution and published our results. We calibrated our anti–factor Xa assay. It is useful when we are unsure of recent exposure to a DOAC and someone comes in bleeding. We can perform this assay as the patient goes to receive a CT scan and usually get usually a result in approximately 30 minutes.

There will be different cutoff points depending on the institution and its calibration. If the anti–factor Xa is <0.1, everyone can feel confident. Depending on the agent—apixaban or rivaroxaban, for us—a value <0.5 indicates that there is fairly low exposure of the DOAC still in the system and that can help us decide whether a reversal agent is needed.

How is the open-label design of the andexanet trial with its strict inclusion criteria better than the multiple retrospective and case studies that have shown a benefit with factor Xa products? With the real-world data regarding the differences in mortality, isn’t it important to note the differences in the patient populations that were being compared, for example, potentially less ill patients in the andexanet group?

When the ANNEXA-4 trial was initially published in 2018, there were more patients in the trial than there had been published in case series in total. Initially, because there had not been clinical studies with prothrombin complex concentrate (PCC) in patients receiving factor Xa inhibitor therapy, as a healthcare system, we almost perpetuated its use. I think we need to give a much higher weight to drug companies that actually talk with the FDA about the patient population and how they will approach the study, what the outcomes are, and regulatory approvals instead of just allowing hospitals and case series because AC Forum guidance in 2016 noted the quality of evidence was so low with PCC that you could just as easily give nothing vs treat with PCC for factor Xa inhibitors. You can see still that there is a group of patients that does not receive any reversal agents.

There are more severe limitations in the quality of evidence of retrospective studies with PCC or even prospective observational studies. First, we have never compared PCC with placebo. Second, there were numerous limitations noted in the COSTA trial, such as not knowing if the patients were even receiving an anticoagulant. That is key: In many of the PCC studies, we do not know if the patient was receiving an anticoagulant. We do not know the levels, and hemostatic efficacy is being measured very late. Hemostatic efficacy is obviously going to be better in a patient who is not anticoagulated or has very minimal anticoagulants in one’s system. That is very different from rigorously designed trials in which we know that the patient has received an anticoagulant.

In the ANNEXA-4 study, all the patients in the efficacy population had baseline anti–factor Xa activity >75 ng/mL, so we know that the patients were anticoagulated therapeutically. The levels were much higher than that; therefore, the levels were likely contributing to the bleeding. It is better to know serial factor Xa levels before, during, and after the bleed and to have serial imaging to see what is happening with the bleed throughout the whole treatment process. This does not occur in the PCC studies.

Is it true that the fixed-dose PCC of 2000 units would not be an effective option for reversal, and it is only for factor replenishment? As a pharmacist, should I even recommend it even though it is in the guidelines?

It depends a lot on what you have available. The guidelines would say if you did not have andexanet alfa, you should use PCC at a fixed dose of 2000 units. Part of that is for convenience and part of it is cost savings. Maybe the weight does not matter as much when you think of volume of distribution. We use quite a bit of fixed dosing when we choose to use a PCC.

Part of the decision is based on the data on whether reversing or reducing a factor Xa and considering PCC reversal agent vs providing factors back to the system that may help with hemostatic efficacy. In general, it is probably safest to follow the guidelines if you have andexanet alfa available, but if you do not, then the PCC at 2000 units is a reasonable alternative approach. I would not expect 2000 units of PCC to completely reverse the DOAC effect in the body, but it may provide factors that would help the patient and help the team improve hemostasis potentially.

Your Thoughts?
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