Reversing DOAC-Associated Major Bleeding—Follow the Data

The Current Marketplace of Anticoagulation
The past decade has seen a revolution in the marketplace of anticoagulation. Five new anticoagulants have been approved. We have new indications for direct oral anticoagulants (DOACs)—specifically rivaroxaban—in patients with peripheral artery disease or coronary artery disease. Rivaroxaban has also been approved for medical thromboprophylaxis for patients at high risk for venous thromboembolism who are not at high risk for bleeding.

At the same time, several anticoagulant reversal agents have been introduced. As a result, we’ve seen better overall better safety in this field, and the incidence of intracranial hemorrhage and other major hemorrhagic events has markedly decreased.

Are We Managing Anticoagulation Reversal Correctly?
We are still learning about hemorrhage management. Of interest, some of these drugs have been on the market for nearly a decade. There has been plenty of time for research and for collection of postmarketing data. During phase I and II trials of the DOAC agents, safety data were collected on treatment of bleeds resulting from DOAC use and on 4-factor prothrombin complex concentrate (4F-PCC). However, if you study data collected since 2014, with factor Xa (FXa) inhibitors (rivaroxaban, apixaban, edoxaban, and betrixaban), there is no effect when you give 4F-PCC on anti-FXa levels—and minimal or no effect on thrombin generation.

It seems that history is repeating itself when we consider how widely 4F-PCC is used in hemorrhage management. Starting around Year 2000, recombinant factor 7A, a component of 4F-PCC and anti-inhibitor coagulant complex, gained widespread use supported by very little data. In reality, a few US Army surgeons were driving its use with anecdotal data and case series supporting them. By 2003, factor 7A was in the Army guidelines even though recommendation for its use were off label. Because its use was so widespread in the Army, surgeons in the civilian world followed suit and it was being used for both patients receiving anticoagulation agents and those not on anticoagulation protocols. There were high rates of arterial and venous thromboembolic events with no clear benefit.

In the modern day, we’ve unfortunately done the same with 4F-PCC, that is, using this complex without the support of well-constructed clinical studies. This is acknowledged in the American Society of Hematology guidelines that recommend 4F-PCC for patients receiving FXa inhibitor with life-threatening bleeding that requires treatment. These guidelines acknowledge that these recommendations come with “very low certainty,” but 4F-PCC is nevertheless the recommendation.

Cost may be one of the primary reasons for use of 4F-PCC. Hospitals and pharmacy and therapeutics committee sometimes justify the use of 4F-PCC because of the cost of agents such as andexanet and idarucizumab. When this is the case, we’re not really looking at the clinical studies and data. The FDA Division Director who oversaw the andexanet review process believed that the effect of andexanet on the surrogate outcome of anti-FXa levels was reasonably likely to predict a clinical benefit (due to its >90% decrease in anti-FXa activity). The belief was that this decrease correlated to better hemostasis and improved morbidity and mortality in bleeding patients receiving apixaban and rivaroxaban who require reversal of anticoagulation. None of the studies that measured anti-FXa activity showed any effect of 4F-PCC in reversing anti-FXa levels—yet we have continued to use it for FXa inhibitor bleeds.

Judicious Off-Label Use of Prescription Drugs
There has been a recent congressional research service report on the Off-Label Use of Prescription Drugs. Let me first say that I support justified off-label use. However, the worst-case scenario for the nation’s health would be the widespread acceptance of a drug for an off-label use that is not supported by sufficient research of its efficacy and safety. Aside from the drug’s potential direct harm, the time spent determining its potential efficacy is time not spent exploring other treatment options.

Unchecked off-label prescribing may also threaten the FDA gold standard of approval. If healthcare professionals had already accepted use of a particular drug into practice through off-label prescribing, there is no incentive for the manufacturer to support multiphase clinical trials and FDA applications. This is precisely what has happened with 4F-PCC. The healthcare systems have justified using 4F-PCC, but we do not have sufficient evidence to prove its worth.

We have known since 2014 that 4F-PCC does not affect anti-FXa levels, and yet the manufacturer has had no incentive to go back and do the appropriate research to support the use of 4F-PCC in patients with bleeds who are receiving anti-FXa agents because the market has supported its use without the research. In many observational studies concerning 4F-PCC and patients with a life-threatening bleed, we are not even sure if the patient was actually receiving an FXa inhibitor because there was no measurement of FXa levels before the 4F-PCC was administered. An additional point concerning how many of these studies were conducted is that the investigators waited and measured hemostatic efficacy at between 18 and 24 hours when one might expect that most of the FXa inhibitor had been excreted by the patient to levels that wouldn’t affect hemostatic efficacy.

A real-world study conducted by Coleman and colleagues makes several very valid points. This was a retrospective chart analysis of hospitalized patients for anticoagulation-related bleeding. There were many limitations in the studies that looked at the use of 4F-PCC in the treatment of intracranial hemorrhages: Definitions of both extent of hemorrhage and outcomes were not consistent; efficacy data were not well defined; and it is unclear in many studies exactly what percentage of patients were even receiving an anticoagulant. Finally, there was very little follow-up with patients out to 30 days or longer as often happens in clinical studies.

The ORANGE study is 3-year prospective registry of anticoagulated patients admitted to UK hospitals with major bleeding who received 4F-PCC. If we compare data from the ANNEXA-4 study (see below) or andexanet to that from ORANGE, intercranial hemorrhage and gastrointestinal bleed mortality are both better with andexanet. We generally don’t compare 2 studies that were not initially designed to be compared. However, this is probably a higher quality of evidence than we see in many of the case series of 4F-PCC.

Current Clinical Trials Supporting Specific Reversing Agent
On the other hand, if we study data on andexanet, we can see that the manufacturer actually pursued clinical studies and has gone through the rigor of getting FDA approval for its data.

ANNEXA-4 was a prospective, open-label, single-arm study in which patients with an episode of acute major bleeding on apixaban, rivaroxaban, edoxaban, or enoxaparin within the previous 18 hours received high- or low-dose andexanet. These patients had levels of apixaban or rivaroxaban ≥75 ng/mL. Results showed a 92% reduction in anti-FXa activity for both apixaban and rivaroxaban. In the efficacy analysis, 79% to 83% of patients had either excellent or good hemostasis with andexanet. And at the time of publication, there were more patients in this study than all the publications combined for the use of 4F-PCC in patients receiving FXa inhibitors.

Likewise, in Reverse-AD, idarucizumab showed positive efficacy in reversing the anticoagulant effects of dabigatran and biomarkers such as direct dilute thrombin time and ecarin clotting time in both medical patients with uncontrolled bleeding and surgical patients who were receiving dabigatran. In medical patients, andexanet has very similar data. Yet, idarucizumab is stocked at thousands and thousands of centers across the nation and andexanet is not. The concern is that we should have on hand a target-specific reversal agent for every agent. That is, we should have idarucizumab to administer if the patient is receiving the thrombin inhibitor dabigatran and we should have andexanet if the patient is receiving the FXa inhibitors rivaroxaban and apixaban.

ANNEXA-1 is an ongoing phase IV (postmarketing) trial. It is the first randomized control trial of a reversal agent (andexanet) vs usual medical care in patients receiving an FXa inhibitor who have intracranial hemorrhage. Usual medical care may be 4F-PCC, it may be treatment with another factor, or it could be no treatment at all. The manufacturer worked with the FDA to have a well-designed trial with very strict entry criteria and patients whom we know are receiving an anticoagulant. There are likewise very strict endpoints (change in NIH Stroke Scale combined with serial imaging and change in FXa inhibitor activity) that are being tracked on a prospective basis. That is very different from gleaning data from charts in a retrospective manner.

Clinical Practice Guidelines Support Use of Reversal Agent–Specific Strategies
The writers of the American College of the Emergency Physician Guidelines felt it was important to differentiate strategies when dealing with bleeding on DOACs. One can administer a reversal agent or one can initiate factor replacement strategy. For instance, if one administers 7F- or 4F-PCC as an option to treat a bleeding patient receiving an FXa inhibitor, that’s really a factor replacement strategy. One is trying to overwhelm the factor inhibition to allow the formation of a clot and gain control over the bleeding. On the other hand, one can use a specific reversal agent (andexanet or idarucizumab) that binds to the FXa inhibitor or thrombin inhibitor and, by binding it, remove it from circulation so that the patient can form a clot. Both of these specific agents have an immediate effect.

The interesting thing is that one can compare the data from very high level, FDA-regulated studies to data on 4F-PCC, which are very low quality. The key takeaway is that a using 4F-PCC for controlling hemorrhages related to FXa inhibitor or thrombin inhibitor use may be the wrong approach.

Your Thoughts?
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