Role Reversal: Hematologists Advise on Bleeding With Newer Anticoagulants

June 22, 2012

June 21, 2012 (Dallas, Texas) — Sophisticated laboratory studies using human blood have shown that the actions of one of the newer anticoagulants, the factor Xa inhibitor apixaban (Eliquis, Pfizer/Bristol-Myers Squibb), could be reversed with existing coagulation factors, although more work is needed to pinpoint the correct doses of these to use, says hematologist Dr Gines Escolar (University of Barcelona, Spain) [1]. This is one of the first studies in this field using human blood; most other research has been conducted in animals, he noted.

Escolar discussed his new findings during an American Heart Association Emerging Science Series webinar, broadcast yesterday. One of the panelists, Dr Neil Zakai (University of Vermont, Burlington), said: "This presentation highlights how complicated hemostasis is. None of these coagulation factors are antidotes; they are ways to bypass the hemostatic system."  It's not clear whether any of them could really reverse bleeding with the newer anticoagulants, he added.            

Although work is under way to develop specific antidotes for these new drugs, "it may take years" until these are on the market, Escolar noted. In the meantime, "there needs to be a protocol for when this is necessary--for example, when surgery needs to be performed or a patient has been involved in an accident."

Escolar also told heartwire that he and his colleagues are now conducting a clinical trial to investigate the ability of two coagulation factors--recombinant factor VIIa and prothrombin complex concentrate (PCC)--to reverse anticoagulation with another factor Xa inhibitor, rivaroxaban (Xarelto, Bayer/Johnson & Johnson), and the direct thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim). He hopes to report some results by the end of the year.

Hematologists Are Cleaning up the Mess; Protocols Are Needed

In a general discussion on the topic, one of the moderators, Dr Elliott Antman (Brigham and Women's Hospital, Boston, MA), noted, "As hematologists, you are called upon to clean up this mess when we have a bleeding problem with these fancy new drugs that we prescribe."

"The fancy new drugs obviously work very well from your point of view, and that's why they've become very popular," another panelist, Dr Cynthia Rutherford (University of Texas Southwestern Medical Center, Dallas), replied. "At UT Southwestern, we are part of a level-one trauma center, and we are getting a lot of questions and trying to give advice without a lot of information. Very sophisticated laboratory studies that we've heard today are useful in understanding what's going on, but we are still struggling to deal with this. We are lacking information in terms of clinical efficacy," she observed.

We are getting a lot of questions and trying to give advice without a lot of information.

Escolar agreed, noting that his department sees two to three patients a week who need reversal of anticoagulation with one of the newer agents for one reason or another. Patients have usually been prescribed the drugs by cardiologists or neurologists, he says, "and sometimes we, and the patients, do not even know which one they are taking." And because they are not taking a vitamin-K antagonist such as warfarin, their details are not fed into the hospital database, so "we need to work on that," he added. "We have confusion, but no big drama. However, we need protocols."

Rutherford went on to detail the procedure in her hospital, which she said evolved from their warfarin reversal protocol. "When someone comes in having taken one of these [new anticoagulants] and has a bleeding risk, we do certain tests. They are very simple: a partial thromboplastin time (PTT) and an activated partial thromboplastin time (aPPT), which are available 24/7, and then we give a standard dose of PCC. We give 50 units/kg, and in fact our protocol--which is an electronic order--actually just gives a standard dose of 4000 units to make it simple, because the people doing this are often ER doctors or surgeons, they are not hematologists."

Our protocol just gives a standard dose of 4000 units [of PCC] to make it simple, because the people doing this are often ER doctors or surgeons, they are not hematologists.

This formula has been in place for a few months, she said, "and we have not had adverse effects from PCC, although it's a big educational issue. A lot of people are still trying to do [reverse anticoagulation] with plasma in these patients who don't tolerate volume very well."

She also believes this approach with PCC will work better for factor Xa inhibitors than for dabigatran and related products. She noted they do measure thrombin time, and if it's normal, she says, the patient has likely excreted the drug. But in the absence of any other strategy, they also use PCC for reversal of dabigatran bleeding, "but we don't know if it helps," she admitted.

Zakai said he understood this approach: "In the absence of something better, you do what you can do."

This is good news for those who are trying to start using these new agents, that there is at least an approach that has been taken in other centers that they can turn to for precedent.

Escolar said, in Spain, "We are conservative right now. We restore red blood cells, give some plasma, but if there is a need for rapid reversal, we try to use PCCs." He pointed out that what happens, however, is "that when these cases succeed they get published, but when they fail they don't."

Rutherford told heartwire that the PCC used in the US is not as strong as that employed elsewhere. "The PCC products available in Canada and Europe contain all four of the vitamin-K–dependent factors (II, VII, IX and X), whereas the PCCs available in the US have pretty low levels of factor VII, so are really considered only a three-factor concentrate," she explained.

Is It the Drug or Something Else?

Another important issue, said Zakai, is whether the drug is causing the bleeding. "If someone comes in after an automobile accident and is on apixaban and has a large hematoma and is bleeding, what part of that bleeding is apixaban contributing to? Instead of saying we are going to reverse everyone quickly, we have to think about whom we need to reverse and what strategy we should use to do it in the safest way possible. These agents are so new, and this highlights how important these in vitro coagulation studies are, because although it's theoretically possible to do a trial in humans where bleeding outcome is looked at, it's impractical."

The panel then discussed whether it was necessary to have some kind of mechanism for knowing how anticoagulated a patient is on the newer drugs, although they acknowledged that this concept would contradict the "selling" point of these novel agents--ie, that patients no longer require monitoring.

The other moderator, AHA past president Dr Robert Bonow (Northwestern University, Chicago, IL,) said: "We do need to come up with a methodology for this, maybe not routinely for every patient in a serial manner, but at least having something that could monitor these patients when they get sick."

And both the hematologists and cardiologists stressed that great care must be taken when considering reversal of anticoagulation.

"People receiving anticoagulants are receiving them for a reason--they are at increased risk of clotting," Bonow said. "We don't want to have a treatment for bleeding that also has a rebound effect that may increase the risk of further thrombosis above the baseline."

Details of in Vitro Studies Reported at Webinar

In his online presentation, Escolar described how blood from healthy volunteers was used in his study, to which apixaban was added, in vitro, at 200 ng/mL, which he noted is about double the concentration of drug expected after normal treatment. Different coagulation factors--recombinant factor VIIa (Novoseven, NovoNordisk) at 270 µg/kg; activated PCC (Feiba, Baxter) at 75 U/kg; and PCC Beriplex (CSL Behring) at 50 IU/kg--were tested in a variety of assays: platelet function at high shear rates (Impact-R, Matis Medical), thrombin generation (TECHNOTHROMBIN, Kordia), viscoelastic parameters (ROTEM, Tem Innovations), and studies with blood flowing through damaged vessels.

Alterations in coagulation were variably compensated or even reversed by the different factor concentrates, although responses to these factors were not homogeneous in all the tests, Escolar noted. He stresses that more work needs to be done to determine the correct doses of these coagulation factors required to reverse anticoagulation, and these doses will not be the same for all the new anticoagulants, with doses likely differing even for different factor Xa inhibitors, he said.

More information on dosing should be gleaned from the clinical trial he and coworkers are conducting, Reversal of the Antithrombotic Action of New Oral Anticoagulants (REVANT). The research will be carried out ex vivo in blood samples obtained from healthy volunteers taking rivaroxaban and dabigatran at doses of proven safety and efficacy and evaluating the ability of PCCs and recombinant factor VIIa to reverse the effects.

Escolar reports receiving a research grant from Bristol-Myers Squibb/Pfizer and honoraria from Bayer Healthcare, Boehringer, and Bristol-Myers Squibb. Zakai has no disclosures. Antman reports receiving a research grant from Daiichi Sankyo. Rutherford is on an end points committee for Genzyme.

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