Reversal Agents in the Age of NOAC Therapy

SEPTEMBER 23, 2018
 

Gary M. Besinque, PharmD, FCSHP; Jaime E. Murillo, MD; Juvairiya Pulicharam, MD; Ralph J. Riello III, PharmD, BCPS; and Peter Salgo, MD, discuss practical implications for using available novel oral anticoagulant therapy reversal agents in patients with nonvalvular atrial fibrillation.

Peter Salgo, MD: What is your clinical experience? Who’s had some clinical experience using Praxbind, which is the reversal agent for Pradaxa [dabigatran etexilate]? Have you used it?

Ralph J. Riello III, PharmD, BCPS: Yes, for sure. We had a patient who showed up with an acute kidney injury. This patient had a bleed after taking the Pradaxa. It was very clear that they’d recently taken Pradaxa. He showed up with a major gastrointestinal bleed. We needed to do whole supportive care, of course—the thresholds, and plasma, and replete everything that you can. It was felt that the patient’s survival would be best if we gave him the antidote. So, we did. It doesn’t necessarily achieve hemostasis right away, but it does suck up all of the available drug. It’s a monoclonal antibody that has 1 job—to find Pradaxa and get it away from thrombin.

Peter Salgo, MD: What you said is important. There are 2 things with any bleed, right? You find the lesion and fix it, but you’ve also got to stop the bleeding. Unless you fix the lesion, it’s not going to stop, right? If you have an intracranial bleed, you probably still need to figure out where you’re bleeding from. That’s not going to fix it.

Ralph J. Riello III, PharmD, BCPS: Right.
Peter Salgo, MD: What is the clinical experience with coagulation factor Xa [recombinant], inactivated-zhzo, which is the reversal agent for apixaban and rivaroxaban. Who has experience with that? Do you use it?

Ralph J. Riello III, PharmD, BCPS: We’re currently in the throes of adding it to formulary. We are devising an acute reversal pathway to kind of implement it into practice. But no, I have not used it yet.

Peter Salgo, MD: Is there any reason to believe it won’t work?

Ralph J. Riello III, PharmD, BCPS: Not at all. It was clinically studied in a large database, and the data, so far, looks good.

Peter Salgo, MD: What do the studies show?

Ralph J. Riello III, PharmD, BCPS: That you have the lowest risk of fatal death and bleeds from the intracranial hemorrhage with an enriched population. 

Gary M. Besinque, PharmD, FCSHP: In the trials that they did with rivaroxaban and apixaban—this was on anti-Xa assay, not necessarily hemostasis, and we all know that there’s sometimes a gap between anti-Xa activity and a control of bleeding—the initial effort was with a bolus and without the infusion. They found that they needed to continue to infuse the drug for an organized clot to form.

Peter Salgo, MD: OK, so this needs to be maintained. 

Gary M. Besinque, PharmD, FCSHP: So the anti-Xa rises back to normal. 

Peter Salgo, MD: OK.

Jaime E. Murillo, MD: My understanding is that they do the bolus and then the 2-hour protocol. They have the ANNEXA-A and ANNEXA-R studies. There are no phase III trials yet for coagulation factor Xa [recombinant], inactivated-zhzo. But, yes, they seem to be very impressive, in terms of their effectiveness.

Peter Salgo, MD: Let’s reverse this. Does the choice of which reversal agent to stop affect the choice of what you prescribe for anticoagulation? How does that work in the real world? 

Gary M. Besinque, PharmD, FCSHP: If you want to keep that security blanket of having a fallback antidote, yes. If you’re going to be using the Praxbind, then you’re going to use the Pradaxa. The other one that you use is coagulation factor Xa, recombinant inactivated-zhzo.

Is it better, in your view, for a patient’s psychological well-being, if you say, “We’re going to put you on this drug. We’ve got the antidote here just in case you need it.” Does that make a difference?

Juvairiya Pulicharam, MD: Yes. Psychologically, for the patient, they want to feel the security, right?

Peter Salgo, MD: So, it helps? 

Juvairiya Pulicharam, MD: Yes.

Peter Salgo, MD: Does it make sense to stop one versus the other? You’ve got a new deal where you don’t pay for anything unless you use it. Is that something anybody can get?

Ralph J. Riello III, PharmD, BCPS: It definitely impacts your decision to prescribe. There are so many commercials now for 1-800-BAD-DRUG, at least in Connecticut. Patients are now coming to me and are saying, “What if I bleed? If I take this medication, some lawyer on TV said I should give him a call.” The fact of the matter is that with the anticoagulant, you may have a bleed. Knowing that you can pull the ripcord if you need to, to reverse it—definitely. It’s comforting to patients. It’s probably more comforting to prescribers. But, it’s important to remember that the kinds of bleeds that these DOACs [direct oral anticoagulants] cause don’t necessarily all necessitate rapid reversal. 

Peter Salgo, MD: Correct. Without being facetious, just for a moment, I see the ads too. I take notice. But, implied in that ad is, “Ifyou’ve been given this drug, please call me.” This implies that you actually call, which implies that you’ve done OK. You can still talk. You can make the phone call. So, one wonders. 

Juvairiya Pulicharam, MD: I think it takes a good partnership, from the manufacturer’s side, to help with that. It’s a collaborative effort.

 
 

Gary M. Besinque, PharmD, FCSHP; Jaime E. Murillo, MD; Juvairiya Pulicharam, MD; Ralph J. Riello III, PharmD, BCPS; and Peter Salgo, MD, discuss practical implications for using available novel oral anticoagulant therapy reversal agents in patients with nonvalvular atrial fibrillation.

Peter Salgo, MD: What is your clinical experience? Who’s had some clinical experience using Praxbind, which is the reversal agent for Pradaxa [dabigatran etexilate]? Have you used it?

Ralph J. Riello III, PharmD, BCPS: Yes, for sure. We had a patient who showed up with an acute kidney injury. This patient had a bleed after taking the Pradaxa. It was very clear that they’d recently taken Pradaxa. He showed up with a major gastrointestinal bleed. We needed to do whole supportive care, of course—the thresholds, and plasma, and replete everything that you can. It was felt that the patient’s survival would be best if we gave him the antidote. So, we did. It doesn’t necessarily achieve hemostasis right away, but it does suck up all of the available drug. It’s a monoclonal antibody that has 1 job—to find Pradaxa and get it away from thrombin.

Peter Salgo, MD: What you said is important. There are 2 things with any bleed, right? You find the lesion and fix it, but you’ve also got to stop the bleeding. Unless you fix the lesion, it’s not going to stop, right? If you have an intracranial bleed, you probably still need to figure out where you’re bleeding from. That’s not going to fix it.

Ralph J. Riello III, PharmD, BCPS: Right.
Peter Salgo, MD: What is the clinical experience with coagulation factor Xa [recombinant], inactivated-zhzo, which is the reversal agent for apixaban and rivaroxaban. Who has experience with that? Do you use it?

Ralph J. Riello III, PharmD, BCPS: We’re currently in the throes of adding it to formulary. We are devising an acute reversal pathway to kind of implement it into practice. But no, I have not used it yet.

Peter Salgo, MD: Is there any reason to believe it won’t work?

Ralph J. Riello III, PharmD, BCPS: Not at all. It was clinically studied in a large database, and the data, so far, looks good.

Peter Salgo, MD: What do the studies show?

Ralph J. Riello III, PharmD, BCPS: That you have the lowest risk of fatal death and bleeds from the intracranial hemorrhage with an enriched population. 

Gary M. Besinque, PharmD, FCSHP: In the trials that they did with rivaroxaban and apixaban—this was on anti-Xa assay, not necessarily hemostasis, and we all know that there’s sometimes a gap between anti-Xa activity and a control of bleeding—the initial effort was with a bolus and without the infusion. They found that they needed to continue to infuse the drug for an organized clot to form.

Peter Salgo, MD: OK, so this needs to be maintained. 

Gary M. Besinque, PharmD, FCSHP: So the anti-Xa rises back to normal. 

Peter Salgo, MD: OK.

Jaime E. Murillo, MD: My understanding is that they do the bolus and then the 2-hour protocol. They have the ANNEXA-A and ANNEXA-R studies. There are no phase III trials yet for coagulation factor Xa [recombinant], inactivated-zhzo. But, yes, they seem to be very impressive, in terms of their effectiveness.

Peter Salgo, MD: Let’s reverse this. Does the choice of which reversal agent to stop affect the choice of what you prescribe for anticoagulation? How does that work in the real world? 

Gary M. Besinque, PharmD, FCSHP: If you want to keep that security blanket of having a fallback antidote, yes. If you’re going to be using the Praxbind, then you’re going to use the Pradaxa. The other one that you use is coagulation factor Xa, recombinant inactivated-zhzo.

Is it better, in your view, for a patient’s psychological well-being, if you say, “We’re going to put you on this drug. We’ve got the antidote here just in case you need it.” Does that make a difference?

Juvairiya Pulicharam, MD: Yes. Psychologically, for the patient, they want to feel the security, right?

Peter Salgo, MD: So, it helps? 

Juvairiya Pulicharam, MD: Yes.

Peter Salgo, MD: Does it make sense to stop one versus the other? You’ve got a new deal where you don’t pay for anything unless you use it. Is that something anybody can get?

Ralph J. Riello III, PharmD, BCPS: It definitely impacts your decision to prescribe. There are so many commercials now for 1-800-BAD-DRUG, at least in Connecticut. Patients are now coming to me and are saying, “What if I bleed? If I take this medication, some lawyer on TV said I should give him a call.” The fact of the matter is that with the anticoagulant, you may have a bleed. Knowing that you can pull the ripcord if you need to, to reverse it—definitely. It’s comforting to patients. It’s probably more comforting to prescribers. But, it’s important to remember that the kinds of bleeds that these DOACs [direct oral anticoagulants] cause don’t necessarily all necessitate rapid reversal. 

Peter Salgo, MD: Correct. Without being facetious, just for a moment, I see the ads too. I take notice. But, implied in that ad is, “Ifyou’ve been given this drug, please call me.” This implies that you actually call, which implies that you’ve done OK. You can still talk. You can make the phone call. So, one wonders. 

Juvairiya Pulicharam, MD: I think it takes a good partnership, from the manufacturer’s side, to help with that. It’s a collaborative effort.

 
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